WO2023064717A2 - Antibodies for sars-cov-2 and uses thereof - Google Patents
Antibodies for sars-cov-2 and uses thereof Download PDFInfo
- Publication number
- WO2023064717A2 WO2023064717A2 PCT/US2022/077810 US2022077810W WO2023064717A2 WO 2023064717 A2 WO2023064717 A2 WO 2023064717A2 US 2022077810 W US2022077810 W US 2022077810W WO 2023064717 A2 WO2023064717 A2 WO 2023064717A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- sars
- cov
- antibody
- seq
- antibodies
- Prior art date
Links
- 241001678559 COVID-19 virus Species 0.000 claims abstract description 113
- 238000000034 method Methods 0.000 claims abstract description 63
- 238000011282 treatment Methods 0.000 claims abstract description 5
- 241000315672 SARS coronavirus Species 0.000 claims description 232
- 108091005634 SARS-CoV-2 receptor-binding domains Proteins 0.000 claims description 135
- 108090000623 proteins and genes Proteins 0.000 claims description 85
- 102000004169 proteins and genes Human genes 0.000 claims description 61
- 239000000203 mixture Substances 0.000 claims description 44
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 21
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 20
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 108091006367 SARS-CoV-2 Spike Subunit S2 Proteins 0.000 claims description 3
- 241000711573 Coronaviridae Species 0.000 abstract description 533
- 102000014914 Carrier Proteins Human genes 0.000 abstract description 38
- 108091008324 binding proteins Proteins 0.000 abstract description 38
- 230000003472 neutralizing effect Effects 0.000 abstract description 3
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 139
- 150000007523 nucleic acids Chemical class 0.000 description 122
- 210000004027 cell Anatomy 0.000 description 102
- 102000039446 nucleic acids Human genes 0.000 description 86
- 108020004707 nucleic acids Proteins 0.000 description 86
- 125000003275 alpha amino acid group Chemical group 0.000 description 80
- 239000013638 trimer Substances 0.000 description 78
- 108090000765 processed proteins & peptides Proteins 0.000 description 56
- 235000018102 proteins Nutrition 0.000 description 56
- 101001024637 Severe acute respiratory syndrome coronavirus 2 Nucleoprotein Proteins 0.000 description 54
- 102000004196 processed proteins & peptides Human genes 0.000 description 52
- 101000953880 Severe acute respiratory syndrome coronavirus 2 Membrane protein Proteins 0.000 description 48
- 229920001184 polypeptide Polymers 0.000 description 46
- 239000000427 antigen Substances 0.000 description 45
- 108091007433 antigens Proteins 0.000 description 44
- 102000036639 antigens Human genes 0.000 description 44
- 235000001014 amino acid Nutrition 0.000 description 42
- 230000027455 binding Effects 0.000 description 42
- 229940024606 amino acid Drugs 0.000 description 39
- 150000001413 amino acids Chemical class 0.000 description 39
- 101000629318 Severe acute respiratory syndrome coronavirus 2 Spike glycoprotein Proteins 0.000 description 38
- 108091028043 Nucleic acid sequence Proteins 0.000 description 36
- 102000040430 polynucleotide Human genes 0.000 description 31
- 108091033319 polynucleotide Proteins 0.000 description 31
- 239000002157 polynucleotide Substances 0.000 description 31
- 239000012634 fragment Substances 0.000 description 30
- 241000282414 Homo sapiens Species 0.000 description 25
- 239000000126 substance Substances 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- 208000015181 infectious disease Diseases 0.000 description 19
- 102100022698 NACHT, LRR and PYD domains-containing protein 1 Human genes 0.000 description 17
- 239000003814 drug Substances 0.000 description 16
- 238000009472 formulation Methods 0.000 description 15
- 238000006386 neutralization reaction Methods 0.000 description 14
- 125000000539 amino acid group Chemical group 0.000 description 13
- 210000003719 b-lymphocyte Anatomy 0.000 description 13
- 210000004962 mammalian cell Anatomy 0.000 description 13
- 239000013598 vector Substances 0.000 description 13
- 210000001744 T-lymphocyte Anatomy 0.000 description 12
- 230000028993 immune response Effects 0.000 description 12
- 229920000642 polymer Polymers 0.000 description 12
- 238000013268 sustained release Methods 0.000 description 12
- 239000012730 sustained-release form Substances 0.000 description 12
- 229940124597 therapeutic agent Drugs 0.000 description 12
- 108060003951 Immunoglobulin Proteins 0.000 description 11
- 101710198474 Spike protein Proteins 0.000 description 11
- 239000000539 dimer Substances 0.000 description 11
- 102000018358 immunoglobulin Human genes 0.000 description 11
- 229920001223 polyethylene glycol Polymers 0.000 description 11
- 241000494545 Cordyline virus 2 Species 0.000 description 10
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 10
- 101000674278 Homo sapiens Serine-tRNA ligase, cytoplasmic Proteins 0.000 description 10
- 102100040516 Serine-tRNA ligase, cytoplasmic Human genes 0.000 description 10
- 241000700605 Viruses Species 0.000 description 10
- -1 amyL Chemical class 0.000 description 10
- 238000009396 hybridization Methods 0.000 description 10
- 239000012678 infectious agent Substances 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 229940096437 Protein S Drugs 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 239000011324 bead Substances 0.000 description 9
- 229920002988 biodegradable polymer Polymers 0.000 description 9
- 239000004621 biodegradable polymer Substances 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 239000013604 expression vector Substances 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 238000006467 substitution reaction Methods 0.000 description 9
- 229920001059 synthetic polymer Polymers 0.000 description 9
- 241000196324 Embryophyta Species 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 210000000130 stem cell Anatomy 0.000 description 8
- 208000023275 Autoimmune disease Diseases 0.000 description 7
- 241000699800 Cricetinae Species 0.000 description 7
- 241000701022 Cytomegalovirus Species 0.000 description 7
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 7
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 7
- 230000000295 complement effect Effects 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 210000004180 plasmocyte Anatomy 0.000 description 7
- 239000002243 precursor Substances 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- 229960005486 vaccine Drugs 0.000 description 7
- 241000588724 Escherichia coli Species 0.000 description 6
- 241000233866 Fungi Species 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- 102000008100 Human Serum Albumin Human genes 0.000 description 6
- 108091006905 Human Serum Albumin Proteins 0.000 description 6
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 6
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 210000003527 eukaryotic cell Anatomy 0.000 description 6
- 229960002885 histidine Drugs 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 239000002773 nucleotide Substances 0.000 description 6
- 125000003729 nucleotide group Chemical group 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 239000004475 Arginine Substances 0.000 description 5
- 241000228245 Aspergillus niger Species 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 5
- 108020004705 Codon Proteins 0.000 description 5
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 5
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 5
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 5
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 5
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 5
- 108010052285 Membrane Proteins Proteins 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 235000004279 alanine Nutrition 0.000 description 5
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 5
- 229920001577 copolymer Polymers 0.000 description 5
- 230000001186 cumulative effect Effects 0.000 description 5
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 5
- 239000007943 implant Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000178 monomer Substances 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 239000001509 sodium citrate Substances 0.000 description 5
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 238000012384 transportation and delivery Methods 0.000 description 5
- 230000003612 virological effect Effects 0.000 description 5
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 4
- 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 4
- 102000053723 Angiotensin-converting enzyme 2 Human genes 0.000 description 4
- 108090000975 Angiotensin-converting enzyme 2 Proteins 0.000 description 4
- 240000006439 Aspergillus oryzae Species 0.000 description 4
- 235000002247 Aspergillus oryzae Nutrition 0.000 description 4
- 208000025721 COVID-19 Diseases 0.000 description 4
- 241000314928 Cordyline virus 1 Species 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 239000004471 Glycine Substances 0.000 description 4
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 4
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 4
- 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 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 108090001074 Nucleocapsid Proteins Proteins 0.000 description 4
- 241000209094 Oryza Species 0.000 description 4
- 108020004511 Recombinant DNA Proteins 0.000 description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 4
- 239000004098 Tetracycline Substances 0.000 description 4
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 4
- 239000004473 Threonine Substances 0.000 description 4
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 4
- 230000010530 Virus Neutralization Effects 0.000 description 4
- 108010048241 acetamidase Proteins 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000000890 antigenic effect Effects 0.000 description 4
- 239000003125 aqueous solvent Substances 0.000 description 4
- 230000001363 autoimmune Effects 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000002299 complementary DNA Substances 0.000 description 4
- 238000005520 cutting process Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 235000013399 edible fruits Nutrition 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 4
- 229940072221 immunoglobulins Drugs 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- 210000003292 kidney cell Anatomy 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 210000002540 macrophage Anatomy 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 230000035515 penetration Effects 0.000 description 4
- 235000004400 serine Nutrition 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 229960002180 tetracycline Drugs 0.000 description 4
- 229930101283 tetracycline Natural products 0.000 description 4
- 235000019364 tetracycline Nutrition 0.000 description 4
- 150000003522 tetracyclines Chemical class 0.000 description 4
- 235000008521 threonine Nutrition 0.000 description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 4
- 235000002374 tyrosine Nutrition 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 101800005309 Carboxy-terminal peptide Proteins 0.000 description 3
- 241000282693 Cercopithecidae Species 0.000 description 3
- 208000035473 Communicable disease Diseases 0.000 description 3
- 206010050685 Cytokine storm Diseases 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- 208000007514 Herpes zoster Diseases 0.000 description 3
- 241000700586 Herpesviridae Species 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 3
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 3
- 241000713666 Lentivirus Species 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 235000007164 Oryza sativa Nutrition 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- 241000283984 Rodentia Species 0.000 description 3
- 101000667982 Severe acute respiratory syndrome coronavirus 2 Envelope small membrane protein Proteins 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 3
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 108090000637 alpha-Amylases Proteins 0.000 description 3
- 102000004139 alpha-Amylases Human genes 0.000 description 3
- 229940024171 alpha-amylase Drugs 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 210000004102 animal cell Anatomy 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 238000002617 apheresis Methods 0.000 description 3
- 235000009582 asparagine Nutrition 0.000 description 3
- 229960001230 asparagine Drugs 0.000 description 3
- 235000003704 aspartic acid Nutrition 0.000 description 3
- 244000052616 bacterial pathogen Species 0.000 description 3
- 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 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 210000000349 chromosome Anatomy 0.000 description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- 206010052015 cytokine release syndrome Diseases 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 235000013922 glutamic acid Nutrition 0.000 description 3
- 239000004220 glutamic acid Substances 0.000 description 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 3
- 235000004554 glutamine Nutrition 0.000 description 3
- 230000013595 glycosylation Effects 0.000 description 3
- 238000006206 glycosylation reaction Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 229920001519 homopolymer Polymers 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 230000001900 immune effect Effects 0.000 description 3
- 230000036039 immunity Effects 0.000 description 3
- 230000002998 immunogenetic effect Effects 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 229960000310 isoleucine Drugs 0.000 description 3
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 229920002521 macromolecule Polymers 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 229930182817 methionine Natural products 0.000 description 3
- 239000003094 microcapsule Substances 0.000 description 3
- 239000011859 microparticle Substances 0.000 description 3
- 239000002088 nanocapsule Substances 0.000 description 3
- 239000002105 nanoparticle Substances 0.000 description 3
- 210000000822 natural killer cell Anatomy 0.000 description 3
- 108010068617 neonatal Fc receptor Proteins 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 230000006320 pegylation Effects 0.000 description 3
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000000750 progressive effect Effects 0.000 description 3
- 210000001236 prokaryotic cell Anatomy 0.000 description 3
- 235000013930 proline Nutrition 0.000 description 3
- 235000009566 rice Nutrition 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 239000004474 valine Substances 0.000 description 3
- 235000013311 vegetables Nutrition 0.000 description 3
- 238000011179 visual inspection Methods 0.000 description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 2
- 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
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- 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 2
- GANZODCWZFAEGN-UHFFFAOYSA-N 5-mercapto-2-nitro-benzoic acid Chemical compound OC(=O)C1=CC(S)=CC=C1[N+]([O-])=O GANZODCWZFAEGN-UHFFFAOYSA-N 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- 241000351920 Aspergillus nidulans Species 0.000 description 2
- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- 244000063299 Bacillus subtilis Species 0.000 description 2
- 235000014469 Bacillus subtilis Nutrition 0.000 description 2
- 240000002791 Brassica napus Species 0.000 description 2
- 235000011299 Brassica oleracea var botrytis Nutrition 0.000 description 2
- 240000003259 Brassica oleracea var. botrytis Species 0.000 description 2
- 235000004977 Brassica sinapistrum Nutrition 0.000 description 2
- 241000282465 Canis Species 0.000 description 2
- 244000025254 Cannabis sativa Species 0.000 description 2
- 108090000565 Capsid Proteins Proteins 0.000 description 2
- 241000701489 Cauliflower mosaic virus Species 0.000 description 2
- 102100023321 Ceruloplasmin Human genes 0.000 description 2
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 description 2
- 102000011022 Chorionic Gonadotropin Human genes 0.000 description 2
- 108010062540 Chorionic Gonadotropin Proteins 0.000 description 2
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 2
- 108091035707 Consensus sequence Proteins 0.000 description 2
- 241000557626 Corvus corax Species 0.000 description 2
- 241000195493 Cryptophyta Species 0.000 description 2
- 240000008067 Cucumis sativus Species 0.000 description 2
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 description 2
- 235000009854 Cucurbita moschata Nutrition 0.000 description 2
- 240000001980 Cucurbita pepo Species 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 241000709661 Enterovirus Species 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 229920001917 Ficoll Polymers 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 108090000288 Glycoproteins Proteins 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 208000001688 Herpes Genitalis Diseases 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 206010020649 Hyperkeratosis Diseases 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 2
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 125000003338 L-glutaminyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C(=O)N([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 241000699673 Mesocricetus auratus Species 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 206010067152 Oral herpes Diseases 0.000 description 2
- 238000012408 PCR amplification Methods 0.000 description 2
- 102000057297 Pepsin A Human genes 0.000 description 2
- 108090000284 Pepsin A Proteins 0.000 description 2
- 102000011755 Phosphoglycerate Kinase Human genes 0.000 description 2
- 102000012288 Phosphopyruvate Hydratase Human genes 0.000 description 2
- 108010022181 Phosphopyruvate Hydratase Proteins 0.000 description 2
- 241000235648 Pichia Species 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- 241000589516 Pseudomonas Species 0.000 description 2
- 241000220324 Pyrus Species 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 241000607142 Salmonella Species 0.000 description 2
- 241000700584 Simplexvirus Species 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 241000194017 Streptococcus Species 0.000 description 2
- 101001099217 Thermotoga maritima (strain ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8) Triosephosphate isomerase Proteins 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 108700019146 Transgenes Proteins 0.000 description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 2
- 108090000848 Ubiquitin Proteins 0.000 description 2
- 102000044159 Ubiquitin Human genes 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000016383 Zea mays subsp huehuetenangensis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 2
- 229960000723 ampicillin Drugs 0.000 description 2
- 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 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000009830 antibody antigen interaction Effects 0.000 description 2
- 230000005875 antibody response Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 210000001772 blood platelet Anatomy 0.000 description 2
- 239000007975 buffered saline Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 2
- 229920006235 chlorinated polyethylene elastomer Polymers 0.000 description 2
- 210000003040 circulating cell Anatomy 0.000 description 2
- 238000000136 cloud-point extraction Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 2
- 229960002086 dextran Drugs 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 231100000676 disease causative agent Toxicity 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 150000004662 dithiols Chemical class 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 201000004946 genital herpes Diseases 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- 210000002443 helper t lymphocyte Anatomy 0.000 description 2
- 239000000833 heterodimer Substances 0.000 description 2
- 229940084986 human chorionic gonadotropin Drugs 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 201000006747 infectious mononucleosis Diseases 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 235000009973 maize Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 210000003593 megakaryocyte Anatomy 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000009126 molecular therapy Methods 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- 239000002077 nanosphere Substances 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 235000021017 pears Nutrition 0.000 description 2
- 229940111202 pepsin Drugs 0.000 description 2
- 210000001322 periplasm Anatomy 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229940071643 prefilled syringe Drugs 0.000 description 2
- 210000001948 pro-b lymphocyte Anatomy 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 101150054232 pyrG gene Proteins 0.000 description 2
- 238000010188 recombinant method Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 2
- 238000002741 site-directed mutagenesis Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- 229940074410 trehalose Drugs 0.000 description 2
- 241000712461 unidentified influenza virus Species 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- DIGQNXIGRZPYDK-WKSCXVIASA-N (2R)-6-amino-2-[[2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-[[(2R,3S)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2R)-2-[[2-[[2-[[2-[(2-amino-1-hydroxyethylidene)amino]-3-carboxy-1-hydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1,5-dihydroxy-5-iminopentylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]hexanoic acid Chemical compound C[C@@H]([C@@H](C(=N[C@@H](CS)C(=N[C@@H](C)C(=N[C@@H](CO)C(=NCC(=N[C@@H](CCC(=N)O)C(=NC(CS)C(=N[C@H]([C@H](C)O)C(=N[C@H](CS)C(=N[C@H](CO)C(=NCC(=N[C@H](CS)C(=NCC(=N[C@H](CCCCN)C(=O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)N=C([C@H](CS)N=C([C@H](CO)N=C([C@H](CO)N=C([C@H](C)N=C(CN=C([C@H](CO)N=C([C@H](CS)N=C(CN=C(C(CS)N=C(C(CC(=O)O)N=C(CN)O)O)O)O)O)O)O)O)O)O)O)O DIGQNXIGRZPYDK-WKSCXVIASA-N 0.000 description 1
- XDIYNQZUNSSENW-UUBOPVPUSA-N (2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O XDIYNQZUNSSENW-UUBOPVPUSA-N 0.000 description 1
- BJMOHHAWJNNXET-REOHCLBHSA-N (2S)-3-hydroxy-2-(sulfoamino)propanoic acid Chemical compound OC[C@@H](C(O)=O)NS(O)(=O)=O BJMOHHAWJNNXET-REOHCLBHSA-N 0.000 description 1
- XWCXASYRBDUEDB-GBXIJSLDSA-N (2S,3R)-3-hydroxy-2-(sulfoamino)butanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NS(O)(=O)=O XWCXASYRBDUEDB-GBXIJSLDSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- OHXPGWPVLFPUSM-KLRNGDHRSA-N 3,7,12-trioxo-5beta-cholanic acid Chemical compound C1CC(=O)C[C@H]2CC(=O)[C@H]3[C@@H]4CC[C@H]([C@@H](CCC(O)=O)C)[C@@]4(C)C(=O)C[C@@H]3[C@]21C OHXPGWPVLFPUSM-KLRNGDHRSA-N 0.000 description 1
- OSJPPGNTCRNQQC-UWTATZPHSA-N 3-phospho-D-glyceric acid Chemical compound OC(=O)[C@H](O)COP(O)(O)=O OSJPPGNTCRNQQC-UWTATZPHSA-N 0.000 description 1
- OSJPPGNTCRNQQC-UHFFFAOYSA-N 3-phosphoglyceric acid Chemical compound OC(=O)C(O)COP(O)(O)=O OSJPPGNTCRNQQC-UHFFFAOYSA-N 0.000 description 1
- GTVVZTAFGPQSPC-UHFFFAOYSA-N 4-nitrophenylalanine Chemical compound OC(=O)C(N)CC1=CC=C([N+]([O-])=O)C=C1 GTVVZTAFGPQSPC-UHFFFAOYSA-N 0.000 description 1
- 101710163881 5,6-dihydroxyindole-2-carboxylic acid oxidase Proteins 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 101710197633 Actin-1 Proteins 0.000 description 1
- 108090000104 Actin-related protein 3 Proteins 0.000 description 1
- 241000701242 Adenoviridae Species 0.000 description 1
- 102000007698 Alcohol dehydrogenase Human genes 0.000 description 1
- 108010021809 Alcohol dehydrogenase Proteins 0.000 description 1
- 102100034044 All-trans-retinol dehydrogenase [NAD(+)] ADH1B Human genes 0.000 description 1
- 101710193111 All-trans-retinol dehydrogenase [NAD(+)] ADH4 Proteins 0.000 description 1
- 241000234282 Allium Species 0.000 description 1
- 240000006108 Allium ampeloprasum Species 0.000 description 1
- 235000005254 Allium ampeloprasum Nutrition 0.000 description 1
- 235000002732 Allium cepa var. cepa Nutrition 0.000 description 1
- 240000002234 Allium sativum Species 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
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 244000144730 Amygdalus persica Species 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 244000099147 Ananas comosus Species 0.000 description 1
- 235000007119 Ananas comosus Nutrition 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 241000534414 Anotopterus nikparini Species 0.000 description 1
- 108010037870 Anthranilate Synthase Proteins 0.000 description 1
- 240000007087 Apium graveolens Species 0.000 description 1
- 235000015849 Apium graveolens Dulce Group Nutrition 0.000 description 1
- 235000010591 Appio Nutrition 0.000 description 1
- 241000219194 Arabidopsis Species 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 241000203069 Archaea Species 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 244000003416 Asparagus officinalis Species 0.000 description 1
- 235000005340 Asparagus officinalis Nutrition 0.000 description 1
- 102000004580 Aspartic Acid Proteases Human genes 0.000 description 1
- 108010017640 Aspartic Acid Proteases Proteins 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 101000961203 Aspergillus awamori Glucoamylase Proteins 0.000 description 1
- 101900318521 Aspergillus oryzae Triosephosphate isomerase Proteins 0.000 description 1
- 241001465318 Aspergillus terreus Species 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 235000007319 Avena orientalis Nutrition 0.000 description 1
- 241000209763 Avena sativa Species 0.000 description 1
- 235000007558 Avena sp Nutrition 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- 241000714230 Avian leukemia virus Species 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- 235000000832 Ayote Nutrition 0.000 description 1
- 101000775727 Bacillus amyloliquefaciens Alpha-amylase Proteins 0.000 description 1
- 101000695691 Bacillus licheniformis Beta-lactamase Proteins 0.000 description 1
- 108010029675 Bacillus licheniformis alpha-amylase Proteins 0.000 description 1
- 101900040182 Bacillus subtilis Levansucrase Proteins 0.000 description 1
- 241000219310 Beta vulgaris subsp. vulgaris Species 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 102100030981 Beta-alanine-activating enzyme Human genes 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 235000011331 Brassica Nutrition 0.000 description 1
- 241000219198 Brassica Species 0.000 description 1
- 235000014698 Brassica juncea var multisecta Nutrition 0.000 description 1
- 235000011293 Brassica napus Nutrition 0.000 description 1
- 235000006008 Brassica napus var napus Nutrition 0.000 description 1
- 240000000385 Brassica napus var. napus Species 0.000 description 1
- 240000007124 Brassica oleracea Species 0.000 description 1
- 235000003899 Brassica oleracea var acephala Nutrition 0.000 description 1
- 235000011301 Brassica oleracea var capitata Nutrition 0.000 description 1
- 235000017647 Brassica oleracea var italica Nutrition 0.000 description 1
- 235000001169 Brassica oleracea var oleracea Nutrition 0.000 description 1
- 235000006618 Brassica rapa subsp oleifera Nutrition 0.000 description 1
- 235000000540 Brassica rapa subsp rapa Nutrition 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 235000004936 Bromus mango Nutrition 0.000 description 1
- 241000589562 Brucella Species 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 241000282836 Camelus dromedarius Species 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 235000012766 Cannabis sativa ssp. sativa var. sativa Nutrition 0.000 description 1
- 235000012765 Cannabis sativa ssp. sativa var. spontanea Nutrition 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 235000002566 Capsicum Nutrition 0.000 description 1
- 235000002568 Capsicum frutescens Nutrition 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 235000009467 Carica papaya Nutrition 0.000 description 1
- 240000006432 Carica papaya Species 0.000 description 1
- 108010051109 Cell-Penetrating Peptides Proteins 0.000 description 1
- 102000020313 Cell-Penetrating Peptides Human genes 0.000 description 1
- 201000006082 Chickenpox Diseases 0.000 description 1
- 241000195585 Chlamydomonas Species 0.000 description 1
- 241001147674 Chlorarachniophyceae Species 0.000 description 1
- 241000195649 Chlorella <Chlorellales> Species 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 241000195628 Chlorophyta Species 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 235000007542 Cichorium intybus Nutrition 0.000 description 1
- 244000298479 Cichorium intybus Species 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 241000193449 Clostridium tetani Species 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 240000007154 Coffea arabica Species 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 102100031673 Corneodesmosin Human genes 0.000 description 1
- 101710139375 Corneodesmosin Proteins 0.000 description 1
- 208000001528 Coronaviridae Infections Diseases 0.000 description 1
- 241000186216 Corynebacterium Species 0.000 description 1
- 241000186226 Corynebacterium glutamicum Species 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 241000709687 Coxsackievirus Species 0.000 description 1
- 102000004420 Creatine Kinase Human genes 0.000 description 1
- 108010042126 Creatine kinase Proteins 0.000 description 1
- 241000219112 Cucumis Species 0.000 description 1
- 235000015510 Cucumis melo subsp melo Nutrition 0.000 description 1
- 235000009852 Cucurbita pepo Nutrition 0.000 description 1
- 235000009804 Cucurbita pepo subsp pepo Nutrition 0.000 description 1
- 241000219130 Cucurbita pepo subsp. pepo Species 0.000 description 1
- 235000003954 Cucurbita pepo var melopepo Nutrition 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 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
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 235000002767 Daucus carota Nutrition 0.000 description 1
- 244000000626 Daucus carota Species 0.000 description 1
- 101100342470 Dictyostelium discoideum pkbA gene Proteins 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 241000199914 Dinophyceae Species 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 241000195634 Dunaliella Species 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 1
- 241001115402 Ebolavirus Species 0.000 description 1
- 241001466953 Echovirus Species 0.000 description 1
- 241000380130 Ehrharta erecta Species 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 101100385973 Escherichia coli (strain K12) cycA gene Proteins 0.000 description 1
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
- 244000004281 Eucalyptus maculata Species 0.000 description 1
- 241000195623 Euglenida Species 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 241000223221 Fusarium oxysporum Species 0.000 description 1
- 101150108358 GLAA gene Proteins 0.000 description 1
- 102000048120 Galactokinases Human genes 0.000 description 1
- 108700023157 Galactokinases Proteins 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- 108700007698 Genetic Terminator Regions Proteins 0.000 description 1
- 241000193385 Geobacillus stearothermophilus Species 0.000 description 1
- 101100001650 Geobacillus stearothermophilus amyM gene Proteins 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 108010007979 Glycocholic Acid Proteins 0.000 description 1
- 108010035713 Glycodeoxycholic Acid Proteins 0.000 description 1
- WVULKSPCQVQLCU-UHFFFAOYSA-N Glycodeoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)C(O)C2 WVULKSPCQVQLCU-UHFFFAOYSA-N 0.000 description 1
- 241000282575 Gorilla Species 0.000 description 1
- 241000219146 Gossypium Species 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101150009006 HIS3 gene Proteins 0.000 description 1
- 101100295959 Halobacterium salinarum (strain ATCC 700922 / JCM 11081 / NRC-1) arcB gene Proteins 0.000 description 1
- 101100246753 Halobacterium salinarum (strain ATCC 700922 / JCM 11081 / NRC-1) pyrF gene Proteins 0.000 description 1
- 244000020551 Helianthus annuus Species 0.000 description 1
- 235000003222 Helianthus annuus Nutrition 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 101710154606 Hemagglutinin Proteins 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 241000709721 Hepatovirus A Species 0.000 description 1
- 208000000903 Herpes simplex encephalitis Diseases 0.000 description 1
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 description 1
- 101000773364 Homo sapiens Beta-alanine-activating enzyme Proteins 0.000 description 1
- 101000913074 Homo sapiens High affinity immunoglobulin gamma Fc receptor I Proteins 0.000 description 1
- 101000917826 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-a Proteins 0.000 description 1
- 101000917824 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-b Proteins 0.000 description 1
- 240000005979 Hordeum vulgare Species 0.000 description 1
- 235000007340 Hordeum vulgare Nutrition 0.000 description 1
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 1
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 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
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 1
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 1
- 108010079585 Immunoglobulin Subunits Proteins 0.000 description 1
- 102000012745 Immunoglobulin Subunits Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102100023915 Insulin Human genes 0.000 description 1
- 102100034349 Integrase Human genes 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- 244000017020 Ipomoea batatas Species 0.000 description 1
- 235000002678 Ipomoea batatas Nutrition 0.000 description 1
- 241001501885 Isochrysis Species 0.000 description 1
- 102100027612 Kallikrein-11 Human genes 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 235000014663 Kluyveromyces fragilis Nutrition 0.000 description 1
- 241001138401 Kluyveromyces lactis Species 0.000 description 1
- 241000235058 Komagataella pastoris Species 0.000 description 1
- 125000003412 L-alanyl group Chemical group [H]N([H])[C@@](C([H])([H])[H])(C(=O)[*])[H] 0.000 description 1
- 125000000570 L-alpha-aspartyl group Chemical group [H]OC(=O)C([H])([H])[C@]([H])(N([H])[H])C(*)=O 0.000 description 1
- 125000002059 L-arginyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])C(=N[H])N([H])[H] 0.000 description 1
- 125000000010 L-asparaginyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(=O)N([H])[H] 0.000 description 1
- 125000000415 L-cysteinyl group Chemical group O=C([*])[C@@](N([H])[H])([H])C([H])([H])S[H] 0.000 description 1
- 125000002061 L-isoleucyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](C([H])([H])[H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000003440 L-leucyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 1
- 125000001176 L-lysyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C([H])([H])C([H])([H])C(N([H])[H])([H])[H] 0.000 description 1
- 125000002435 L-phenylalanyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000002842 L-seryl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])O[H] 0.000 description 1
- 125000000769 L-threonyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](O[H])(C([H])([H])[H])[H] 0.000 description 1
- 125000002707 L-tryptophyl group Chemical group [H]C1=C([H])C([H])=C2C(C([C@](N([H])[H])(C(=O)[*])[H])([H])[H])=C([H])N([H])C2=C1[H] 0.000 description 1
- 125000003798 L-tyrosyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 description 1
- 125000003580 L-valyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(C([H])([H])[H])(C([H])([H])[H])[H] 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
- 235000003228 Lactuca sativa Nutrition 0.000 description 1
- 240000008415 Lactuca sativa Species 0.000 description 1
- 241000589248 Legionella Species 0.000 description 1
- 208000007764 Legionnaires' Disease Diseases 0.000 description 1
- 235000014647 Lens culinaris subsp culinaris Nutrition 0.000 description 1
- 244000043158 Lens esculenta Species 0.000 description 1
- 241000186779 Listeria monocytogenes Species 0.000 description 1
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 0.000 description 1
- 235000007688 Lycopersicon esculentum Nutrition 0.000 description 1
- 101150068888 MET3 gene Proteins 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 235000014826 Mangifera indica Nutrition 0.000 description 1
- 240000007228 Mangifera indica Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000712079 Measles morbillivirus Species 0.000 description 1
- 240000004658 Medicago sativa Species 0.000 description 1
- 235000017587 Medicago sativa ssp. sativa Nutrition 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 102000003792 Metallothionein Human genes 0.000 description 1
- 108090000157 Metallothionein Proteins 0.000 description 1
- 241000205276 Methanosarcina Species 0.000 description 1
- 241000713333 Mouse mammary tumor virus Species 0.000 description 1
- 241000711386 Mumps virus Species 0.000 description 1
- 240000005561 Musa balbisiana Species 0.000 description 1
- 235000018290 Musa x paradisiaca Nutrition 0.000 description 1
- 241000186367 Mycobacterium avium Species 0.000 description 1
- 241000186363 Mycobacterium kansasii Species 0.000 description 1
- 241000713883 Myeloproliferative sarcoma virus Species 0.000 description 1
- 102000003505 Myosin Human genes 0.000 description 1
- 108060008487 Myosin Proteins 0.000 description 1
- 241001467460 Myxogastria Species 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- HFDZHKBVRYIMOG-QMMMGPOBSA-N N-sulfotyrosine Chemical compound OS(=O)(=O)N[C@H](C(=O)O)CC1=CC=C(O)C=C1 HFDZHKBVRYIMOG-QMMMGPOBSA-N 0.000 description 1
- RFDAIACWWDREDC-UHFFFAOYSA-N Na salt-Glycocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)C(O)C2 RFDAIACWWDREDC-UHFFFAOYSA-N 0.000 description 1
- 241000224474 Nannochloropsis Species 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 108010006232 Neuraminidase Proteins 0.000 description 1
- 102000005348 Neuraminidase Human genes 0.000 description 1
- 101100022915 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cys-11 gene Proteins 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 108090000913 Nitrate Reductases Proteins 0.000 description 1
- 102100039019 Nuclear receptor subfamily 0 group B member 1 Human genes 0.000 description 1
- BZQFBWGGLXLEPQ-UHFFFAOYSA-N O-phosphoryl-L-serine Natural products OC(=O)C(N)COP(O)(O)=O BZQFBWGGLXLEPQ-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 102000007981 Ornithine carbamoyltransferase Human genes 0.000 description 1
- 101710113020 Ornithine transcarbamylase, mitochondrial Proteins 0.000 description 1
- 102100037214 Orotidine 5'-phosphate decarboxylase Human genes 0.000 description 1
- 108010055012 Orotidine-5'-phosphate decarboxylase Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 1
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 241000520272 Pantoea Species 0.000 description 1
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 108010088535 Pep-1 peptide Proteins 0.000 description 1
- 239000006002 Pepper Substances 0.000 description 1
- 108010077524 Peptide Elongation Factor 1 Proteins 0.000 description 1
- 244000025272 Persea americana Species 0.000 description 1
- 235000008673 Persea americana Nutrition 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 235000016761 Piper aduncum Nutrition 0.000 description 1
- 240000003889 Piper guineense Species 0.000 description 1
- 235000017804 Piper guineense Nutrition 0.000 description 1
- 235000008184 Piper nigrum Nutrition 0.000 description 1
- 240000004713 Pisum sativum Species 0.000 description 1
- 235000010582 Pisum sativum Nutrition 0.000 description 1
- 208000002151 Pleural effusion Diseases 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 208000007048 Polymyalgia Rheumatica Diseases 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 108010068086 Polyubiquitin Proteins 0.000 description 1
- 241000700625 Poxviridae Species 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102100036691 Proliferating cell nuclear antigen Human genes 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 101710176177 Protein A56 Proteins 0.000 description 1
- 102000007568 Proto-Oncogene Proteins c-fos Human genes 0.000 description 1
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 1
- 241000125945 Protoparvovirus Species 0.000 description 1
- 241000196250 Prototheca Species 0.000 description 1
- 235000009827 Prunus armeniaca Nutrition 0.000 description 1
- 244000018633 Prunus armeniaca Species 0.000 description 1
- 235000006029 Prunus persica var nucipersica Nutrition 0.000 description 1
- 235000006040 Prunus persica var persica Nutrition 0.000 description 1
- 244000017714 Prunus persica var. nucipersica Species 0.000 description 1
- 241000168225 Pseudomonas alcaligenes Species 0.000 description 1
- 241001112090 Pseudovirus Species 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000711798 Rabies lyssavirus Species 0.000 description 1
- 102000004879 Racemases and epimerases Human genes 0.000 description 1
- 108090001066 Racemases and epimerases Proteins 0.000 description 1
- 244000088415 Raphanus sativus Species 0.000 description 1
- 235000006140 Raphanus sativus var sativus Nutrition 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- 241000712907 Retroviridae Species 0.000 description 1
- 241000235403 Rhizomucor miehei Species 0.000 description 1
- 101000968489 Rhizomucor miehei Lipase Proteins 0.000 description 1
- 240000005384 Rhizopus oryzae Species 0.000 description 1
- 235000013752 Rhizopus oryzae Nutrition 0.000 description 1
- 241000206572 Rhodophyta Species 0.000 description 1
- 101100394989 Rhodopseudomonas palustris (strain ATCC BAA-98 / CGA009) hisI gene Proteins 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical class N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- 108010039491 Ricin Proteins 0.000 description 1
- 241000606701 Rickettsia Species 0.000 description 1
- 241000714474 Rous sarcoma virus Species 0.000 description 1
- 241000710799 Rubella virus Species 0.000 description 1
- 241001092459 Rubus Species 0.000 description 1
- 235000017848 Rubus fruticosus Nutrition 0.000 description 1
- 240000007651 Rubus glaucus Species 0.000 description 1
- 235000011034 Rubus glaucus Nutrition 0.000 description 1
- 235000009122 Rubus idaeus Nutrition 0.000 description 1
- 108091005609 SARS-CoV-2 Spike Subunit S1 Proteins 0.000 description 1
- 108091005774 SARS-CoV-2 proteins Proteins 0.000 description 1
- 241000235070 Saccharomyces Species 0.000 description 1
- 101900354623 Saccharomyces cerevisiae Galactokinase Proteins 0.000 description 1
- 244000253911 Saccharomyces fragilis Species 0.000 description 1
- 235000018368 Saccharomyces fragilis Nutrition 0.000 description 1
- 240000000111 Saccharum officinarum Species 0.000 description 1
- 235000007201 Saccharum officinarum Nutrition 0.000 description 1
- 108010084592 Saporins Proteins 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- 241000195663 Scenedesmus Species 0.000 description 1
- 241000235346 Schizosaccharomyces Species 0.000 description 1
- 241000235347 Schizosaccharomyces pombe Species 0.000 description 1
- 101100022918 Schizosaccharomyces pombe (strain 972 / ATCC 24843) sua1 gene Proteins 0.000 description 1
- 244000136421 Scirpus acutus Species 0.000 description 1
- 241000209056 Secale Species 0.000 description 1
- 235000007238 Secale cereale Nutrition 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 241001291279 Solanum galapagense Species 0.000 description 1
- 240000003768 Solanum lycopersicum Species 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 244000061458 Solanum melongena Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 240000003829 Sorghum propinquum Species 0.000 description 1
- 235000011684 Sorghum saccharatum Nutrition 0.000 description 1
- 235000009337 Spinacia oleracea Nutrition 0.000 description 1
- 244000300264 Spinacia oleracea Species 0.000 description 1
- 244000107946 Spondias cytherea Species 0.000 description 1
- 235000009184 Spondias indica Nutrition 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000193985 Streptococcus agalactiae Species 0.000 description 1
- 101100309436 Streptococcus mutans serotype c (strain ATCC 700610 / UA159) ftf gene Proteins 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 241001505901 Streptococcus sp. 'group A' Species 0.000 description 1
- 241000193990 Streptococcus sp. 'group B' Species 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 241000187432 Streptomyces coelicolor Species 0.000 description 1
- 101100370749 Streptomyces coelicolor (strain ATCC BAA-471 / A3(2) / M145) trpC1 gene Proteins 0.000 description 1
- 241000187391 Streptomyces hygroscopicus Species 0.000 description 1
- 241000187398 Streptomyces lividans Species 0.000 description 1
- 235000021536 Sugar beet Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 210000000173 T-lymphoid precursor cell Anatomy 0.000 description 1
- 238000011053 TCID50 method Methods 0.000 description 1
- WBWWGRHZICKQGZ-UHFFFAOYSA-N Taurocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)C(O)C2 WBWWGRHZICKQGZ-UHFFFAOYSA-N 0.000 description 1
- 241000196321 Tetraselmis Species 0.000 description 1
- 101100157012 Thermoanaerobacterium saccharolyticum (strain DSM 8691 / JW/SL-YS485) xynB gene Proteins 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- 108700009124 Transcription Initiation Site Proteins 0.000 description 1
- 102100037116 Transcription elongation factor 1 homolog Human genes 0.000 description 1
- 108020004566 Transfer RNA Proteins 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- 102000005924 Triose-Phosphate Isomerase Human genes 0.000 description 1
- 108700015934 Triose-phosphate isomerases Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 101710152431 Trypsin-like protease Proteins 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 101150050575 URA3 gene Proteins 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 244000000188 Vaccinium ovalifolium Species 0.000 description 1
- 206010046980 Varicella Diseases 0.000 description 1
- 241000700647 Variola virus Species 0.000 description 1
- 229940126222 Veklury Drugs 0.000 description 1
- 241000711975 Vesicular stomatitis virus Species 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 241000235013 Yarrowia Species 0.000 description 1
- 241000235015 Yarrowia lipolytica Species 0.000 description 1
- 241000235017 Zygosaccharomyces Species 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 108700010877 adenoviridae proteins Proteins 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 108010045649 agarase Proteins 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 235000020224 almond Nutrition 0.000 description 1
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000009833 antibody interaction Effects 0.000 description 1
- 238000009175 antibody therapy Methods 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 102000025171 antigen binding proteins Human genes 0.000 description 1
- 108091000831 antigen binding proteins Proteins 0.000 description 1
- 230000009831 antigen interaction Effects 0.000 description 1
- 230000014102 antigen processing and presentation of exogenous peptide antigen via MHC class I Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 101150008194 argB gene Proteins 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 101150103518 bar gene Proteins 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000003139 biocide Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000001815 biotherapy 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
- 235000021029 blackberry Nutrition 0.000 description 1
- 210000002459 blastocyst Anatomy 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229940098773 bovine serum albumin Drugs 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
- 239000006227 byproduct Substances 0.000 description 1
- 235000009120 camo Nutrition 0.000 description 1
- TWFZGCMQGLPBSX-UHFFFAOYSA-N carbendazim Chemical compound C1=CC=C2NC(NC(=O)OC)=NC2=C1 TWFZGCMQGLPBSX-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 235000005607 chanvre indien Nutrition 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 1
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 239000013611 chromosomal DNA Substances 0.000 description 1
- 229940069078 citric acid / sodium citrate Drugs 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 235000016213 coffee Nutrition 0.000 description 1
- 235000013353 coffee beverage Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000011018 current good manufacturing practice Methods 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 101150005799 dagA gene Proteins 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229960002997 dehydrocholic acid Drugs 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 229950006137 dexfosfoserine Drugs 0.000 description 1
- 229960000633 dextran sulfate Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 229940061607 dibasic sodium phosphate Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- ZQPPMHVWECSIRJ-MDZDMXLPSA-N elaidic acid Chemical compound CCCCCCCC\C=C\CCCCCCCC(O)=O ZQPPMHVWECSIRJ-MDZDMXLPSA-N 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000002308 embryonic cell Anatomy 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- DUDCYUDPBRJVLG-UHFFFAOYSA-N ethoxyethane methyl 2-methylprop-2-enoate Chemical compound CCOCC.COC(=O)C(C)=C DUDCYUDPBRJVLG-UHFFFAOYSA-N 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 210000004700 fetal blood Anatomy 0.000 description 1
- 210000005254 filamentous fungi cell Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 102000034287 fluorescent proteins Human genes 0.000 description 1
- 108091006047 fluorescent proteins Proteins 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000004459 forage Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 210000004475 gamma-delta t lymphocyte Anatomy 0.000 description 1
- 235000004611 garlic Nutrition 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 230000024924 glomerular filtration Effects 0.000 description 1
- 108010061330 glucan 1,4-alpha-maltohydrolase Proteins 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 description 1
- 229940099347 glycocholic acid Drugs 0.000 description 1
- WVULKSPCQVQLCU-BUXLTGKBSA-N glycodeoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 WVULKSPCQVQLCU-BUXLTGKBSA-N 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 238000011194 good manufacturing practice Methods 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000000185 hemagglutinin Substances 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 239000011487 hemp Substances 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 235000008216 herbs Nutrition 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 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
- 108010002685 hygromycin-B kinase Proteins 0.000 description 1
- 108091008915 immune receptors Proteins 0.000 description 1
- 102000027596 immune receptors Human genes 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000017555 immunoglobulin mediated immune response Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 229940031154 kluyveromyces marxianus Drugs 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000029226 lipidation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 101150039489 lysZ gene Proteins 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 210000001806 memory b lymphocyte Anatomy 0.000 description 1
- 210000003071 memory t lymphocyte Anatomy 0.000 description 1
- 229960003151 mercaptamine Drugs 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 229940045641 monobasic sodium phosphate Drugs 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 238000002887 multiple sequence alignment Methods 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 239000003471 mutagenic agent Substances 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 210000000581 natural killer T-cell Anatomy 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 101150095344 niaD gene Proteins 0.000 description 1
- 239000002777 nucleoside Chemical class 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 108090000021 oryzin Proteins 0.000 description 1
- 230000000065 osmolyte Effects 0.000 description 1
- 239000002357 osmotic agent Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 101150019841 penP gene Proteins 0.000 description 1
- 108010043655 penetratin Proteins 0.000 description 1
- MCYTYTUNNNZWOK-LCLOTLQISA-N penetratin Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CC=CC=C1 MCYTYTUNNNZWOK-LCLOTLQISA-N 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
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 108010082527 phosphinothricin N-acetyltransferase Proteins 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- USRGIUJOYOXOQJ-GBXIJSLDSA-N phosphothreonine Chemical compound OP(=O)(O)O[C@H](C)[C@H](N)C(O)=O USRGIUJOYOXOQJ-GBXIJSLDSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 235000021018 plums Nutrition 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 229920000765 poly(2-oxazolines) Polymers 0.000 description 1
- 229920000724 poly(L-arginine) polymer Polymers 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920001583 poly(oxyethylated polyols) Polymers 0.000 description 1
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 1
- 229920002946 poly[2-(methacryloxy)ethyl phosphorylcholine] polymer Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000223 polyglycerol Polymers 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000004845 protein aggregation Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000000455 protein structure prediction Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 235000015136 pumpkin Nutrition 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Chemical class O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- 101150025220 sacB gene Proteins 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity 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
- 150000003354 serine derivatives Chemical class 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 210000000717 sertoli cell Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 125000005629 sialic acid group Chemical group 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- PTLRDCMBXHILCL-UHFFFAOYSA-M sodium arsenite Chemical compound [Na+].[O-][As]=O PTLRDCMBXHILCL-UHFFFAOYSA-M 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- 229940048086 sodium pyrophosphate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 235000020354 squash Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- 238000005382 thermal cycling Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 150000003587 threonine derivatives Chemical class 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 238000012876 topography Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000002463 transducing effect Effects 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014599 transmission of virus Effects 0.000 description 1
- UYPYRKYUKCHHIB-UHFFFAOYSA-N trimethylamine N-oxide Chemical compound C[N+](C)(C)[O-] UYPYRKYUKCHHIB-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 101150016309 trpC gene Proteins 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 150000003668 tyrosines Chemical class 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- 244000052613 viral pathogen Species 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 101150110790 xylB gene Proteins 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
- C07K16/1002—Coronaviridae
- C07K16/1003—Severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2 or Covid-19]
-
- 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
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Definitions
- SARS-CoV-2 is the causative agent, the virus that causes, COVID-19. It is novel coronavirus that first infected humans starting in December 2019. At the time of the filing of this application SARS-CoV-2 had infected at least 1,279,546 person in the United States, and had killed at least 76,527 persons. There is a present unmet medical need for therapies to treat SARS-CoV-2 infections and reduce the morbidity and mortality of this disease in the United States and around the world.
- the disclosure relates to antibodies obtained from subjects who acquired immunity to coronavirus, SARS-CoV-2. Over a thousand human antibodies have been obtained from these subjects in a screening to identify antibody clones that bound to targets from SARS-CoV-2.
- the targets or mixture of targets used to identify the anti-SARS-CoV-2 antibodies were SARS-CoV-2 Spike 1 Protein (SI), SARS-CoV-2 Spike 2 Protein (S2), SARS-CoV-2 Receptor Binding Domain, SARS-CoV-2 Spike 1 Protein OR SARS-CoV-2 Spike 2 Protein (S1+S2), SARS-CoV-2 Spike 1 Protein OR SARS-CoV-2 S2 Protein OR SARS-CoV-2 Membrane Protein OR SARS-CoV-2 Envelope Protein (S1+S2+E+M).
- SI SARS-CoV-2 Spike 1 Protein
- S2 SARS-CoV-2 Spike 2 Protein
- SARS-CoV-2 Receptor Binding Domain SARS-CoV-2 Spike
- the nucleic acid and amino acid sequences of the variable region heavy chains and light chains for these anti-SARS-CoV-2 antibodies are disclosed herein.
- the antibodies can be monoclonal, and can be fully human antibodies, chimeric antibodies, or CDR- grafted antibodies.
- the antibodies can be full length or and antibody fragment.
- Antibody fragments include any of the well-known formats or types, including for example, antigen-binding fragments (Fab), single chain variable fragments (scFv) and “third generation” (3G).
- Specific antibodies disclosed herein include, for example, anti-SARS-CoV-2 (SC2) antibody 3417 (SC2 Ab 3417 or 3417), SC2 antibody 3387 (3387), SC2 antibody 3705 (3705), SC2 antibody 3388 (3388), SC2 antibody 3396 (3396), SC2 antibody 3908 (3908), SC2 antibody 3916 (3916), SC2 antibody 3929 (3929), SC2 antibody 3940 (3940), SC2 antibody 4021 (4021).
- SC2 antibody 3387 (3387) and SC2 antibody 3705 (3705) have shown affinity for various variants of SARS-CoV-2 now present in the population.
- SC2 antibody 3387 (3387), SC2 antibody 3705 (3705), SC antibody 3396, and SC2 antibody 3417 (3417) have also shown neutralizing activity against SARS-CoV-2.
- the anti-SARS-CoV-2 antibodies can be full length antibodies such as, for example, an IgG (e.g., IgGl, IgG2, IgG3, or IgG4), an IgM, an IgA, an IgD, or an IgE.
- the anti-SARS-CoV-2 antibody can be an antibody fragment such as, for example, a Fab, F(ab’)2, single chain antibody (scFv), Fv, or other antibody fragments made from recombinant nucleic acids encoding fragments of the antibody chains.
- the antibody fragments can also be made by digestion of an anti-SARS- CoV-2 antibody to generate a smaller fragment.
- the anti-SARS-CoV-2 antibody can be obtained from a B-cell, a plasma cell, a B memory cell, a pre-B-cell or a progenitor B-cell.
- compositions and formulations described here can comprise one or more of the anti-SARS- CoV-2 antibodies for administration to a subject.
- the compositions with the anti-SARS-CoV-2 antibodies can also include other drugs or agents for treatment of the subject.
- the anti-SARS-CoV-2 antibody compositions can include analgesics, other antiviral drugs, other antiviral antibodies, and/or agents that reduce symptoms caused by infection with SARS-CoV-2.
- Methods described herein use the anti-SARS-CoV-2 antibodies to neutralize (e.g., in vitro or in vivo or both) the SARS-CoV-2 virus and inhibit the virus from infecting cells.
- the methods can be used to treat subjects with active infections from SARS-CoV-2 and thereby reduce the symptoms in a subject, time of infection of the subject, or transmission of virus to others by the infected subject.
- the methods can also be used prophylactically to reduce, inhibit, or prevent infection of a subject by the SARS-CoV-2 virus.
- FIG. 1 (3) shows a work flow chart for obtaining clones expressing a desired antigen binding protein using a single cell selecting device.
- FIG. 2 shows a bar graph of virus neutralization by the anti-SARS-CoV2 antibodies.
- FIG. 3 shows a line graph of virus neutralization by the anti-SARS-CoV2 antibodies.
- FIG. 4 shows a line graph of neutralization of the delta variant by SARS-CoV-2 antibody (SC2 antibody 3387).
- FIG. 5 shows a line graph of neutralization activity of Wuhan-1 by anti-SARS-CoV-2 antibodies.
- FIG. 5 shows bar graphs of viral titer in Hamsters inoculated with SARS-CoV-2 after prophylactic treatment with an anti-SARS-CoV-2 antibody.
- an “antibody” refers to a protein functionally defined as a binding protein and structurally defined as comprising an amino acid sequence that is recognized as being derived from the framework region of an immunoglobulin encoding gene of an animal producing antibodies.
- An antibody can consist of one or more polypeptides substantially encoded by immunoglobulin genes or fragments of immunoglobulin genes.
- the recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as myriad immunoglobulin variable region genes.
- Light chains are classified as either kappa or lambda.
- Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
- a typical immunoglobulin (antibody) structural unit is known to comprise a tetramer.
- Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD).
- the N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
- the terms variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chains respectively.
- Antibodies exist as intact immunoglobulins or as a number of well-characterized fragments.
- pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'2, a dimer of Fab which itself is a light chain joined to VH-CH1 by a disulfide bond.
- the F(ab)'2 may be reduced under mild conditions to break the disulfide linkage in the hinge region thereby converting the (Fab')2 dimer into an Fab' monomer.
- the Fab' monomer is essentially an Fab with part of the hinge region (see, Fundamental Immunology, W. E. Paul, ed., Raven Press, N.Y.
- antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that fragments can be synthesized de novo either chemically or by utilizing recombinant DNA methodology.
- the term antibody as used herein also includes antibody fragments either produced by the modification of whole antibodies or synthesized using recombinant DNA methodologies.
- Preferred antibodies include VH-VL dimers, including single chain antibodies (antibodies that exist as a single polypeptide chain), such as single chain Fv antibodies (sFv or scFv) in which a variable heavy and a variable light region are joined together (directly or through a peptide linker) to form a continuous polypeptide.
- the single chain Fv antibody is a covalently linked VH-VL heterodimer which may be expressed from a nucleic acid including VH- and VL- encoding sequences either joined directly or joined by a peptide-encoding linker (e.g., Huston, et al. Proc. Nat. Acad. Sci. USA, 85:5879-5883, 1988). While the VH and VL are connected to each as a single polypeptide chain, the VH and VL domains associate non-covalently. Alternatively, the antibody can be another fragment. Other fragments can also be generated, including using recombinant techniques.
- Fab molecules can be displayed on phage if one of the chains (heavy or light) is fused to g3 capsid protein and the complementary chain exported to the periplasm as a soluble molecule.
- the two chains can be encoded on the same or on different replicons; the two antibody chains in each Fab molecule assemble post-translationally and the dimer is incorporated into the phage particle via linkage of one of the chains to g3p (see, e.g., U.S. Pat. No: 5,733,743).
- the scFv antibodies and a number of other structures converting the naturally aggregated, but chemically separated light and heavy polypeptide chains from an antibody V region into a molecule that folds into a three-dimensional structure substantially similar to the structure of an antigen-binding site are known to those of skill in the art (see e.g., U.S. Pat. Nos. 5,091,513, 5,132,405, and 4,956,778).
- the scFv is a diabody as described in Holliger et al., Proc. Nat’ 1 Acad. Sci. vol. 90, pp. 6444-6448 (1993), which is incorporated by reference in its entirety for all purposes.
- antibodies include all those that have been displayed on phage or generated by recombinant technology using vectors where the chains are secreted as soluble proteins, e.g., scFv, Fv, Fab, pr (Fab')2 or generated by recombinant technology using vectors where the chains are secreted as soluble proteins.
- Antibodies can also include diantibodies and miniantibodies.
- Antibodies of the invention also include heavy chain dimers, such as antibodies from camelids. Since the VH region of a heavy chain dimer IgG in a camelid does not have to make hydrophobic interactions with a light chain, the region in the heavy chain that normally contacts a light chain is changed to hydrophilic amino acid residues in a camelid. VH domains of heavy-chain dimer IgGs are called VHH domains.
- the diversity of antibody repertoire is determined by the complementary determining regions (CDR) 1, 2, and 3 in the VH or VHH regions.
- CDR3 in the camel VHH region is characterized by its relatively long length averaging 16 amino acids (Muyldermans et al., 1994, Protein Engineering 7(9): 1129). This is in contrast to CDR3 regions of antibodies of many other species.
- the CDR3 of mouse VH has an average of 9 amino acids.
- HA hemagglutinin
- NB neuraminidase
- NA antigenic glycoproteins located on the surface of influenza viruses. These glycoproteins are responsible for the binding the virus to the cell that is to be infected and processes that result in infection with the virus.
- naturally occurring means that the components are encoded by a single gene that was not altered by recombinant means and that pre-exists in an organism, e.g., in an antibody library that was created from naive cells or cells that were exposed to an antigen.
- the term “antigen” refers to substances that are capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, such as, with specific antibodies or specifically sensitized T-lymphocytes, or both.
- Antigens may be soluble substances, such as toxins and foreign proteins, or particulates, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (epitopes) combines with the antibody or a specific receptor on a lymphocyte. More broadly, the term "antigen" may be used to refer to any substance to which an antibody binds, or for which antibodies are desired, regardless of whether the substance is immunogenic. For such antigens, antibodies may be identified by recombinant methods, independently of any immune response.
- epitope refers to the site on an antigen or hapten to which specific B cells and/or T cells respond.
- the term is also used interchangeably with "antigenic determinant” or "antigenic determinant site”.
- Epitopes include that portion of an antigen or other macromolecule capable of forming a binding interaction that interacts with the variable region binding pocket of an antibody.
- binding specificity of an antibody refers to the identity of the antigen to which the antibody binds, preferably to the identity of the epitope to which the antibody binds.
- chimeric polynucleotide means that the polynucleotide comprises regions which are wild-type and regions which are mutated. It may also mean that the polynucleotide comprises wild-type regions from one polynucleotide and wild-type regions from another related polynucleotide.
- chimeric polynucleotide means that the polynucleotide comprises regions which are wild-type and regions which are mutated. It may also mean that the polynucleotide comprises wild-type regions from one polynucleotide and wild-type regions from another related polynucleotide.
- CDR complementarity-determining region
- Framework region refers to the region of the V domain that flank the CDRs.
- the positions of the CDRs and framework regions can be determined using various well known definitions in the art, e.g., Kabat, Chothia, international ImMunoGeneTics database (IMGT), and AbM (see, e.g., Johnson et al., supra; Chothia & Lesk, 1987, Canonical structures for the hypervariable regions of immunoglobulins. J. Mol. Biol. 196, 901-917; Chothia C. et al., 1989, Conformations of immunoglobulin hypervariable regions. Nature 342, 877-883; Chothia C.
- conservative substitution refers to substitution of an amino acid in a polypeptide with a functionally, structurally or chemically similar natural or unnatural amino acid.
- the following groups each contain natural amino acids that are conservative substitutions for one another:
- hapten is a small molecule that, when attached to a larger carrier such as a protein, can elicit an immune response in an organism, e.g., such as the production of antibodies that bind specifically to it (in either the free or combined state).
- a “hapten” is able to bind to a preformed antibody, but may fail to stimulate antibody generation on its own.
- hapten includes modified amino acids, either naturally occurring or non-naturally occurring.
- hapten includes naturally occurring modified amino acids such as phosphotyrosine, phosphothreonine, phosphoserine, or sulphated residues such as sulphated tyrosine (sulphotyrosine), sulphated serine (sulphoserine), or sulphated threonine (sulphothreonine); and also include non-naturally occurring modified amino acids such as p-nitro-phenylalanine.
- heterologous when used with reference to portions of a polynucleotide indicates that the nucleic acid comprises two or more subsequences that are not normally found in the same relationship to each other in nature.
- the nucleic acid is typically recombinantly produced, having two or more sequences, e.g., from unrelated genes arranged to make a new functional nucleic acid.
- a “heterologous” polypeptide or protein refers to two or more subsequences that are not found in the same relationship to each other in nature.
- the term “host cell” refers to a prokaryotic or eukaryotic cell into which the vectors of the invention may be introduced, expressed and/or propagated.
- a microbial host cell is a cell of a prokaryotic or eukaryotic micro-organism, including bacteria, yeasts, microscopic fungi and microscopic phases in the life-cycle of fungi and slime molds.
- Typical prokaryotic host cells include various strains of E. coli.
- Typical eukaryotic host cells are yeast or filamentous fungi, or mammalian cells, such as Chinese hamster ovary cells, murine NIH 3T3 fibroblasts, human embryonic kidney 193 cells, or rodent myeloma or hybridoma cells.
- the term “immunological response” to a composition or vaccine is the development in the host of a cellular and/or antibody-mediated immune response to a composition or vaccine of interest.
- an “immunological response” includes but is not limited to one or more of the following effects: the production of antibodies, B cells, helper T cells, and/or cytotoxic T cells, directed specifically to an antigen or antigens included in the composition or vaccine of interest.
- the host will display either a therapeutic or protective immunological response such that resistance to new infection will be enhanced and/or the clinical severity of the disease reduced. Such protection will be demonstrated by either a reduction or lack of symptoms normally displayed by an infected host, a quicker recovery time and/or a lowered viral titer in the infected host.
- isolated refers to a nucleic acid or polypeptide separated not only from other nucleic acids or polypeptides that are present in the natural source of the nucleic acid or polypeptide, but also from polypeptides, and preferably refers to a nucleic acid or polypeptide found in the presence of (if anything) only a solvent, buffer, ion, or other component normally present in a solution of the same.
- isolated and purified do not encompass nucleic acids or polypeptides present in their natural source.
- mammal refers to warm-blooded vertebrate animals all of which possess hair and suckle their young.
- percentage of sequence identity and “percentage homology” are used interchangeably herein to refer to comparisons among polynucleotides or polypeptides, and are determined by comparing two optimally aligned sequences over a comparison window, where the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence for optimal alignment of the two sequences.
- the percentage may be calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.
- the percentage may be calculated by determining the number of positions at which either the identical nucleic acid base or amino acid residue occurs in both sequences or a nucleic acid base or amino acid residue is aligned with a gap to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.
- Those of skill in the art appreciate that there are many established algorithms available to align two sequences.
- Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman, Adv Appl Math. 2:482, 1981; by the homology alignment algorithm of Needleman and Wunsch, J Mol Biol. 48:443, 1970; by the search for similarity method of Pearson and Lipman, Proc Natl Acad Sci. USA 85:2444, 1988; by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the GCG Wisconsin Software Package), or by visual inspection (see generally, Current Protocols in Molecular Biology, F. M. Ausubel et al., eds., Greene Publishing Associates, Inc. and John Wiley & Sons, Inc., (1995 Supplement).
- BLAST and BLAST 2.0 algorithms are described in Altschul et al., J. Mol. Biol. 215:403-410, 1990; and Altschul et al., Nucleic Acids Res. 25(17):3389-3402, 1977; respectively.
- Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information website.
- BLAST for amino acid sequences can use the BLASTP program with default parameters, e.g., a wordlength (W) of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff, Proc Natl Acad Sci. USA 89: 10915, 1989).
- Exemplary determination of sequence alignment and % sequence identity can also employ the BESTFIT or GAP programs in the GCG Wisconsin Software package (Accelrys, Madison WI), using default parameters provided.
- pharmaceutically acceptable refers to a substance (e.g., an active ingredient or an excipient) that is suitable for use in contact with the tissues and organs of a subject without excessive irritation, allergic response, immunogenicity and toxicity, is commensurate with a reasonable benefit/risk ratio, and is effective for its intended use.
- a “pharmaceutically acceptable” excipient or carrier of a pharmaceutical composition is also compatible with the other ingredients of the composition.
- protein protein
- peptide polypeptide
- polypeptide fragment polymers of amino acid residues of any length.
- the polymer can be linear or branched, it may comprise modified amino acids or amino acid analogs, and it may be interrupted by chemical moieties other than amino acids.
- the terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling or bioactive component.
- the term “protracting moiety” means a molecule that can be attached to a polypeptide (e.g., an antibody light and/or heavy chain) to increase its molecular weight so that the polypeptide’s residence time in the blood (and/or serum) is increased.
- the protracting moiety can increase the serum/blood half-life of the polypeptide.
- the increased half-life or residence time can be the result of, for example, reduced glomerular filtration by the kidney, and/or reduced uptake by the liver, and/or reduced binding and removal by immune binding proteins, etc.
- a protracting moiety can be, for example, another polypeptide, a polymer (e.g., synthetic polymer, natural polymer, etc.), etc.
- the term “purified” means that the indicated nucleic acid or polypeptide is present in the substantial absence of other biological macromolecules, e.g., polynucleotides, proteins, and the like.
- the polynucleotide or polypeptide is purified such that it constitutes at least 95% by weight, more preferably at least 99.8% by weight, of the indicated biological macromolecules present (but water, buffers, and other small molecules, especially molecules having a molecular weight of less than 1000 daltons, can be present).
- RBD SARS-CoV-2 receptor binding domain
- SI SARS-CoV-2 Spike 1 protein
- SARS-CoV-2 Spike 2 protein SARS-CoV-2 protein
- EP SARS-CoV-2 Envelope Proteins
- MP SARS-CoV-2 Membrane Protein
- recombinant nucleic acid refers to a nucleic acid in a form not normally found in nature. That is, a recombinant nucleic acid is flanked by a nucleotide sequence not naturally flanking the nucleic acid or has a sequence not normally found in nature. Recombinant nucleic acids can be originally formed in vitro by the manipulation of nucleic acid by restriction endonucleases, or alternatively using such techniques as polymerase chain reaction.
- nucleic acid once a recombinant nucleic acid is made and reintroduced into a host cell or organism, it will replicate non-recombinantly, i.e., using the in vivo cellular machinery of the host cell rather than in vitro manipulations; however, such nucleic acids, once produced recombinantly, although subsequently replicated non-recombinantly, are still considered recombinant for the purposes of the invention.
- recombinant polypeptide refers to a polypeptide expressed from a recombinant nucleic acid, or a polypeptide that is chemically synthesized in vitro.
- the term “recombinant variant” refers to any polypeptide differing from naturally occurring polypeptides by amino acid insertions, deletions, and substitutions, created using recombinant DNA techniques. Guidance in determining which amino acid residues may be replaced, added, or deleted without abolishing activities of interest, such as enzymatic or binding activities, may be found by comparing the sequence of the particular polypeptide with that of homologous peptides and minimizing the number of amino acid sequence changes made in regions of high homology.
- amino acid “substitutions” are the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, i.e., conservative amino acid replacements.
- Amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved.
- nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine;
- polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine;
- positively charged (basic) amino acids include arginine, lysine, and histidine; and negatively charged (acidic) amino acids include aspartic acid and glutamic acid.
- SARS-CoV-2 means the Severe acute respiratory syndrome coronavirus 2 that cause the illness COVID-19.
- SARS-CoV-2 includes the strains and sub-strains of coronavirus that are arising during this outbreak of SARS-CoV-2.
- stringent hybridization conditions refers to hybridizing in 50% formamide at 5XSSC at a temperature of 42 °C and washing the filters in 0.2XSSC at 60 °C. (1XSSC is 0.15M NaCl, 0.015M sodium citrate.) Stringent hybridization conditions also encompasses low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50 °C; hybridization with a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42 °C; or 50% formamide, 5XSSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8)
- substantially homologous or “substantially identical” in the context of two polypeptides or polynucleotides refers to two or more sequences or subsequences that have at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid or nucleic acid residue identity, when compared and aligned for maximum correspondence, as measured using a sequence comparison algorithm or by visual inspection.
- the terms “substantially homologous” or “substantially identical” can mean at least about 70% amino acid or nucleic acid residue identity.
- substantially homologous or “substantially identical” can mean at least about 85% amino acid or nucleic acid residue identity.
- the substantial homology or identity can exist over a region of the sequences that is at least about 20, 30, 40, 50, 100, 150 or 200 residues in length.
- the sequences can be substantially homologous or identical over the entire length of either or both comparison biopolymers.
- Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman, Adv. Appl. Math., 2:482 (1981); by the homology alignment algorithm of Needleman and Wunsch, J. Mol. Biol., 48:443 (1970); by the search for similarity method of Pearson and Lipman, Proc. Natl. Acad. Sci. USA, 85:2444 (1988); by computerized implementations of these algorithms (e.g., GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, Madison, Wisconsin); or by visual inspection.
- PILEUP creates a multiple sequence alignment from a group of related sequences using progressive, pairwise alignments to show relationship and percent sequence identity. It also plots a tree or dendogram showing the clustering relationships used to create the alignment. PILEUP uses a simplification of the progressive alignment method of Feng and Doolittle, J. Mol. Evol., 35:351-360 (1987). The method used is similar to the method described by Higgins and Sharp, CABIOS, 5: 151-153 (1989). The program can align up to about 300 sequences, each having a maximum length of about 5,000 nucleotides or amino acids.
- the multiple alignment procedure begins with the pairwise alignment of the two most similar sequences, producing a cluster of two aligned sequences. This cluster is then aligned to the next most related sequence or cluster of aligned sequences. Two clusters of sequences are aligned by a simple extension of the pairwise alignment of two individual sequences. The final alignment is achieved by a series of progressive, pairwise alignments.
- the program is run by designating specific sequences and their amino acid or nucleotide coordinates for regions of sequence comparison and by designating the program parameters. For example, a reference sequence can be compared to other test sequences to determine the percent sequence identity relationship using the following parameters: default gap weight (3.00), default gap length weight (0.10), and weighted end gaps.
- Another algorithm that is useful for generating multiple alignments of sequences is Clustal W (see, e.g., Thompson et al., Nucleic Acids Research, 22:4673-4680 [1994]).
- HSPs high scoring sequence pairs
- the word hits are then extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always ⁇ 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction is halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached.
- the BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment.
- the BLASTP program uses as defaults, e.g., a wordlength (W) of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff, Proc. Natl. Acad. Sci. LISA, 89: 10915 [1989]).
- the BLAST algorithm In addition to calculating percent sequence identity, the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul, Proc. Natl. Acad. Sci. USA, 90:5873-5787 [1993]).
- One measure of similarity provided by the BLAST algorithm is the smallest sum probability [P(N)], which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance.
- P(N) the smallest sum probability
- a polynucleotide is considered similar to a reference sequence if the smallest sum probability in a comparison of the test polynucleotide to the reference polynucleotide is less than about 0.1, 0.01 or 0.001.
- a polypeptide can be substantially homologous or identical to a second polypeptide if the two polypeptides differ only by conservative amino acid substitutions.
- Two nucleic acid sequences can be substantially homologous or identical if the two polynucleotides hybridize to each other under stringent conditions, or under highly stringent conditions, as described herein.
- terapéuticaally effective amount refers to an amount of a compound that, when administered to a subject, is sufficient to prevent, reduce the risk of developing, delay the onset of, slow the progression or cause regression of the medical condition being treated, or to alleviate to some extent the medical condition or one or more symptoms or complications of that condition.
- therapeutically effective amount also refers to an amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, organ, system, animal or human which is sought by a researcher, veterinarian, medical doctor or clinician.
- Antibodies are immune binding proteins that are structurally defined as comprising an amino acid sequence recognized as being derived from the framework region of an immunoglobulin.
- An antibody can consist of one or more polypeptides substantially encoded by immunoglobulin genes or fragments of immunoglobulin genes.
- the immunoglobulin genes can include, for example, the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as myriad immunoglobulin variable region genes.
- Antibody light chains can be classified as either kappa or lambda.
- Antibody heavy chains can be classified as gamma, mu, alpha, delta, or epsilon, which in turn can define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
- Antibodies can exist as intact immunoglobulins or as a number of well-known fragments. Pepsin digests an antibody below the disulfide linkages in the hinge region and can produce F(ab)'2, a dimer of Fab which itself is a light chain joined to VH-CH1 by a disulfide bond. The F(ab)'2 may be reduced under mild conditions to break the disulfide linkage in the hinge region thereby converting the (Fab')2 dimer into Fab' monomers.
- the Fab' monomer can be an Fab with part of the hinge region (see, Fundamental Immunology, W. E. Paul, ed., Raven Press, N.Y. (1993), which is incorporated by reference in its entirety for all purposes).
- Antibody fragments can also be synthesized de novo either chemically or by utilizing recombinant DNA methodology.
- Antibodies can include VH-VL dimers, including single chain antibodies (antibodies that exist as a single polypeptide chain), diabodies, or single chain Fv antibodies (sFv or scFv) in which a variable heavy and a variable light region are joined together (directly or through a peptide linker) to form a continuous polypeptide, (e.g., Huston, et al. Proc. Nat. Acad. Sci. USA, 85:5879-5883, 1988, which is incorporated by reference in its entirety for all purposes).
- VH-VL dimers including single chain antibodies (antibodies that exist as a single polypeptide chain), diabodies, or single chain Fv antibodies (sFv or scFv) in which a variable heavy and a variable light region are joined together (directly or through a peptide linker) to form a continuous polypeptid
- Antibodies can also include other fragments, including, for example, Fab molecules displayed on phage if one of the chains (heavy or light) is fused to g3 capsid protein and the complementary chain exported to the periplasm as a soluble molecule, (e.g., U.S. Pat. No: 5,733,743, which is incorporated by reference in its entirety for all purposes).
- the antibody can be an scFv antibody or a number of other structures converting the naturally aggregated, but chemically separated light and heavy polypeptide chains from an antibody V region into a molecule that folds into a three dimensional structure substantially similar to the structure of an antigen-binding site are known to those of skill in the art (e.g., U.S. Pat. Nos.
- the scFv can be a diabody as described in Holliger et al., Proc. Nat’l Acad. Sci. vol. 90, pp. 6444-6448 (1993), which is incorporated by reference in its entirety for all purposes.
- Antibodies include all those that have been displayed on phage or generated by recombinant technology using vectors where the chains are secreted as soluble proteins, e.g., scFv, Fv, Fab, pr (Fab'X Antibodies can also include miniantibodies.
- the antibody can be obtained from a B-cell, a plasma cell, a B memory cell, a pre-B-cell or a progenitor B-cell.
- the antibodies can be monoclonal, and can be fully human antibodies, chimeric antibodies, or CDR-grafted antibodies.
- the antibodies can be full length or and antibody fragment.
- Antibody fragments include any of the well-known formats or types, including for example, antigen-binding fragments (Fab), single chain variable fragments (scFv) and “third generation” (3G). Nelson, MAbs 2010, 2:77-83, doi: 10.4161/mabs.2.1.10786, which is incorporated by reference in its entirety for all purposes.
- F(ab')2, Fab, Fab' and Fv are examples of antigen-binding fragments that can be generated from the variable region of IgG and IgM.
- Anti-SARS-CoV-2 antibody 3417 can have a variable region comprised of a heavy chain with the amino acid sequence of:
- This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of: ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT CGCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGCTGAAGCCCTCGCAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGTCTCCATCAGAAATAGTAATTACTTCTGGAATTG GATCCGGCGGCCCGCCGGGAAGGGACTGGAGTGGATTGGGCGTATGCATAGTGGTG GGACCACCAATTACAATCCCTCAAGAGTCGGGTCACCGTGTCAAGTGACGCGG CCAGGAACCAGTTCTCCCTGGAGTTGACCTCTGTGACCGCCGCAGACACGGCCGTGT ATTACTGTGCGAGAGATGACCCCCTTAACCGGTTCGCTGCTTTTCAAATCTGGGGCCG AGGGACACTGGTCACCGTCTTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCTGTCTGGGGCCG AGGGACACTGGTCACCGTCTT
- Anti-SARS-CoV-2 antibody 3417 can have a variable region comprised of a light chain with the amino acid sequence of:
- This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
- Anti-SARS-CoV-2 antibody 3387 can have a variable region comprised of a heavy chain with the amino acid sequence of:
- This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of: ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT CGCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGATGCAAGTGGGGGCCTCAGTGA AGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAGCTATGGTATCAGCTGGGTGCG ACAGGCCCCCGGACAAGGGCTTGAGTGGATGGGATGGATCAACACTTACAATGGTA ACACAAACTATGCACAGAAGCTCCAGGGCAGAGTCACCATGACCACAGACACATCC ACGACCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTAT TACTGTGCGAGAGTCGCTGTAGGATATTGCAGTGGTGGTAGCTGCTACTACTTTGACT ACTGGGGCCAGGGAACCCTGGTCACCGTCCTCAGCTAGCACCAAGGGCCCATCGG TCTTCCCCCTGGCACCCTCCTCCA
- Anti-SARS-CoV-2 antibody 3387 can have a variable region comprised of a light chain with the amino acid sequence of:
- This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
- Anti-SARS-CoV-2 antibody 3705 is a single chain antibody with the amino acid sequence of:
- This amino acid sequence can be encoded in a nucleic acid sequence of:
- Anti-SARS-CoV-2 antibody 3388 can have a variable region comprised of a heavy chain with the amino acid sequence of:
- This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of:
- Anti-SARS-CoV-2 antibody 3388 can have a variable region comprised of a light chain with the amino acid sequence of:
- This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
- Anti-SARS-CoV-2 antibody 3396 can have a variable region comprised of a heavy chain with the amino acid sequence of:
- This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of:
- Anti-SARS-CoV-2 antibody 3396 can have a variable region comprised of a light chain with the amino acid sequence of:
- This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
- Anti-SARS-CoV-2 antibody 3908 can have a variable region comprised of a heavy chain with the amino acid sequence of:
- This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of: ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT CGGAGGTGCAGCTGGTGGAGTCTAGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGA GACTCTCCTGTGCAGCCACTGGATTCACCCTCAGTAGCTTCGACATGCACTGGGTCCG CCAAGCTACAGGAAAAGGTCTGGAGTGGGTCTCAGCTATTGGTACTGCTGGTGACAC ATACTATCCAGGCTCCGTGAAGGGCCGATTCACCATCTCCAGAGAAAATGCCAAGAA CTCCTTGTATCTTCAAATGAACAGCCTGAGAGCCGGGGACACGGCTGTGTATTACTGT GCAAGAGGGACCTGGCTCCGAGATTACAATTTTTGGAGTGGTTATAATTACTACTTTG ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCAT CGGTCTTCCCCCTGGCACCCTCC
- AAATGA SEQ ID NO: 20
- Anti-SARS-CoV-2 antibody 3908 can have a variable region comprised of a light chain with the amino acid sequence of:
- This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
- Anti-SARS-CoV-2 antibody 3916 can have a variable region comprised of a heavy chain with the amino acid sequence of: MYRMQLLSCIALSLALVTNSQVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIR QPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARQ RGQRITMVRLKRDWFDPWGQGTL VTVS S ASTKGPS VFPL APS SKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIE
- This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of: ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT CGCAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAGCTGGATCCG CCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGGAAATCAATCATAGTGGAAGCA CCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGA ACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCTGTGTATTACTG TGCGAGGCAAAGGGGGCAACGTATTACTATGGTTCGGCTAAAACGGGACTGGTTCGA
- Anti-SARS-CoV-2 antibody 3916 can have a variable region comprised of a light chain with the amino acid sequence of:
- This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
- Anti-SARS-CoV-2 antibody 3929 can have a variable region comprised of a heavy chain with the amino acid sequence of:
- Anti-SARS-CoV-2 antibody 3929 can have a variable region comprised of a light chain with the amino acid sequence of:
- This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
- Anti-SARS-CoV-2 antibody 3940 can have a variable region comprised of a heavy chain with the amino acid sequence of:
- This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of:
- Anti-SARS-CoV-2 antibody 3940 can have a variable region comprised of a light chain with the amino acid sequence of:
- This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
- Anti-SARS-CoV-2 antibody 4021 can have a variable region comprised of a heavy chain with the amino acid sequence of:
- This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of: ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT
- Anti-SARS-CoV-2 antibody 4021 can have a variable region comprised of a light chain with the amino acid sequence of:
- This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
- SC2 antibody 3417 binds to Sino CoV2 SI (spike protein 1), NAC CoV2 SI, Sino CoV2
- SC2 antibody 3387 binds to SI and RBD.
- SC2 antibody 3388 also cross reacts with SARS1 SI and SARS1 RBD.
- SC2 antibody 3908 also cross reacts with Coll SARS1 S1+S2 and Coll SARS1 RBD.
- SC2 antibody 3916 binds to NAC CoV2 SI, Sino CoV2 S2, Sino CoV2 S1+S2, Sino CoV2 RBD, NAC CoV2 Mosaic, ProteinTech Membrane Protein and ProteinTech Nucleocapsid.
- SC2 antibody 3916 also cross reacts with Coll SARS1 S1+S2 and Coll SARS1 RBD.
- SC2 antibody 3929 binds to Sino CoV2 RBD.
- SC2 antibody 3388 also cross reacts with Sino SARS1 SI and Coll SARS1 RBD.
- the anti-SARS-CoV-2 antibodies 3417 (SEQ ID NO: 1 and 3), 3387 (SEQ ID NO: 5 and 7), 3388 (SEQ ID NO: 11 and 13), 3396 (SEQ ID NO: 15 and 17), 3908 (SEQ ID NO: 19 and 21), 3916 (SEQ ID NO: 23 and 25), 3929 (SEQ ID NO: 27 and 29), 3940 (SEQ ID NO: 31 and 33), 4021 (SEQ ID NO: 35 and 37), and 3705 (SEQ ID NO: 9) also include variable regions having amino acid sequences that have 99%, 95%, 90%, 80% or 70% sequence identity with one of the heavy chains from variable region SEQ ID NO: 1, 5, 11, 15, 19, 23, 27, 31 or 35, and a light chain that has 99%, 95%, 90%, 80% or 70% sequence identity with one light chains from variable region SEQ ID NO: 3, 7, 13, 17, 21, 25, 29, 33, or 37.
- CDRs from anti-SARS-CoV-2 antibodies 3417 (SEQ ID NO: 1 and 3), 3387 (SEQ ID NO: 5 and 7), 3388 (SEQ ID NO: 11 and 13), 3396 (SEQ ID NO: 15 and 17), 3908 (SEQ ID NO: 19 and 21), 3916 (SEQ ID NO: 23 and 25), 3929 (SEQ ID NO: 27 and 29), 3940 (SEQ ID NO: 31 and 33), 4021 (SEQ ID NO: 35 and 37), and 3705 (SEQ ID NO: 9) can be use to make CDR grafted antibodies known in the art.
- AGCTCCAACATTGGGAATAAATAT light chain CDR1 (SEQ ID NO: 42)
- the CDRs of SC2 antibody 3387 are:
- CAGAGTGTTAGCAACAAC light chain CDR1 (SEQ ID NO: 48)
- CAGCAGTATAATGACTGGCCTCCGTCTTGGACG light chain CDR3 (SEQ ID NO: 50)
- the CDRs of SC2 antibody 3388 are:
- the CDRs of SC2 antibody 3396 are:
- the CDRs of SC2 antibody 3908 are:
- the CDRs of SC2 antibody 3916 are:
- GGTGGGTCCTTCAGTGGTTACTAC heavy chain CDR1 (SEQ ID NO: 69)
- ATCAATCATAGTGGAAGCACC heavy chain CDR2 (SEQ ID NO: 70)
- the CDRs of SC2 antibody 3929 are:
- AGTTCCAATATGGGAAGTAATTTT light chain CDR1 (SEQ ID NO: 78)
- the CDRs of SC2 antibody 3940 are:
- ATCTATCCTGGTGACTCTGATACC heavy chain CDR2 (SEQ ID NO: 82)
- AGCACAAAAAAAGGAACAGGTAACGAT light chain CDR1 (SEQ ID NO: 84)
- the CDRs of SC2 antibody 4021 are:
- GGATTCAGCTTCAGTAGCACCTAT heavy chain CDR1 (SEQ ID NO: 87)
- ATTTATACCGATGGTGCGGCA heavy chain CDR2 (SEQ ID NO: 88)
- the CDRs of SC2 antibody 3705 are:
- GGTTATACCTTTACCAGCTATGGA heavy chain CDR1 (SEQ ID NO: 93) ATTAATACTTACAATGGGAACACA heavy chain CDR2 (SEQ ID NO: 94) GCGCGCGTCGCTGTAGGCTATTGCAGTGGTGGCAGCTGCTACTACTTCGATTAC heavy chain CDR3 (SEQ ID NO: 95)
- CAGAGTGTTAGCAACAAC light chain CDR1 (SEQ ID NO: 96) GGTGCATCC light chain CDR2 (SEQ ID NO: 97) CAGCAGTATAATGACTGGCCTCCGTCTTGGACG light chain CDR3 (SEQ ID NO: 98)
- An anti-SARS-CoV-2 antibody can also include a variable region made from a nucleic acid encoding a heavy chain that has 99%, 95%, 90%, 80% or 70% sequence identity with one of the nucleic acids encoding a heavy chain (SEQ ID NO: 2, 6, 12, 16, 20, 24, 28, 32, or 36), and a nucleic acid encoding a light chain that has 99%, 95%, 90%, 80% or 70% sequence identity with one of the nucleic acids encoding a light chain (SEQ ID NO: 4, 8, 14, 18, 22, 26, 30, 34, or 38).
- An anti- SARS-CoV-2 antibody can also include a variable region made from a nucleic acid encoding a heavy chain that hybridizes under stringent hybridization conditions with one of the nucleic acids encoding one of the heavy chains (SEQ ID NO: 2, 6, 12, 16, 20, 24, 28, 32 or 36), and a nucleic acid encoding a light chain that hybridizes under stringent hybridization conditions with one of the nucleic acids encoding one of the light chains (SEQ ID NO: 4, 8, 14, 18, 22, 26, 30, 34, or 38).
- An anti-SARS-CoV-2 antibody can be made with a variable region selected from variable regions encoded by antibodies 1-402. (See Table 1) The heavy chains are encoded by the odd numbered SEQ ID Nos. and the light chains are encoded by the even numbered SEQ ID NOs of each variable region pair.
- anti-SARS-CoV-2 variable region The identifier for each anti-SARS-CoV-2 variable region is in second column labeled Ab, so anti-SARS-CoV-2 variable region (1) is encoded by SEQ ID Nos: 159 (heavy chain) and 160 (light chain), anti-SARS-CoV-2 variable region (2) is encoded by SEQ ID Nos: 161 (heavy chain) and 162 (light chain), anti-SARS-CoV-2 variable region (3) is encoded by SEQ ID Nos: 163 (heavy chain) and 164 (light chain), etc.
- Anti-SARS-CoV-2 antibody 3910 can have a variable region comprised of a heavy chain with the amino acid sequence of:
- This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of: CAAGTGCAGCTGCAGGAGTCCGGCTCCGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCACCTGCGCTGTCTCTGGTGTCTCCATGAGCACTGGTGATTACTCCTGGAGCTGGA TCCGGCGGCCACCAGGGAAGGGCCTGGAGTGGATTGGTTACATCTTCCTAGGTGGGA
- Anti-SARS-CoV-2 antibody 3910 can have a variable region comprised of a light chain with the amino acid sequence of:
- This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
- the CDRs of SC2 antibody 3910 are:
- Anti-SARS-CoV-2 antibody 3915 can have a variable region comprised of a heavy chain with the amino acid sequence of:
- This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of:
- Anti-SARS-CoV-2 antibody 3915 can have a variable region comprised of a light chain with the amino acid sequence of:
- This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
- the CDRs of SC2 antibody 3915 are:
- Anti-SARS-CoV-2 antibody 3945 can have a variable region comprised of a heavy chain with the amino acid sequence of:
- NPSLKSRLTISIDRSKNQFSLGLSSVTAADTAVYYCARVRRNTSGSFSTGHFDYWGQGTL VTVSS (SEQ ID NO: 119)
- This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of:
- Anti-SARS-CoV-2 antibody 3945 can have a variable region comprised of a light chain with the amino acid sequence of:
- This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
- the CDRs of SC2 antibody 3945 are:
- ATCTATGATAGTGGGATCACC heavy chain CDR2 (SEQ ID NO: 124)
- Anti-SARS-CoV-2 antibody 3947 can have a variable region comprised of a heavy chain with the amino acid sequence of:
- VTVSS (SEQ ID NO: 129)
- This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of: CAGCTGCAGCTGCAGGAGTCCGGCTCAGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCACCTGCGCTGTCTCTGGTGGCTCCGTCAGCAGTGGTGGTTATTCCTGGAGCTGGA
- Anti-SARS-CoV-2 antibody 3947 can have a variable region comprised of a light chain with the amino acid sequence of:
- This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
- the CDRs of SC2 antibody 3947 are:
- ATCTATGATAGTGGGATCACC heavy chain CDR2 (SEQ ID NO: 134)
- Anti-SARS-CoV-2 antibody 3969 can have a variable region comprised of a heavy chain with the amino acid sequence of:
- This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of:
- Anti-SARS-CoV-2 antibody 3969 can have a variable region comprised of a light chain with the amino acid sequence of:
- This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
- Anti-SARS-CoV-2 antibody 4083 can have a variable region comprised of a heavy chain with the amino acid sequence of:
- This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of:
- Anti-SARS-CoV-2 antibody 4083 can have a variable region comprised of a light chain with the amino acid sequence of:
- This light chain amino acid sequence can be encoded in a nucleic acid sequence of: CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGTCCCAGGACAGAAGGTCACC ATCTCCTGCTCTGGAAACAACTCCAATATTGGAAATAATCTTGTATCCTGGTACCAGC AGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATAACAATAATAGGCGACCATCAG GGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCAC CGGACTCCAGACTGGGGACGAGGCCGCTTATTATTGCGCAGCAAGGGATAGCAGCCT GAGTGCTGTGGTGTTCGGCGGAGGGACCAAACTGACCGTCCTA (SEQ ID NO: 152)
- the CDRs of SC2 antibody 4083 are:
- GGTGGCTCCGTCAGCAGTGGTGGTTATTCC heavy chain CDR1 (SEQ ID NO: 153)
- ATCTATGATAGTGGGATCACC heavy chain CDR2 (SEQ ID NO: 154)
- GCCAGAGTTCGGCGGAATACTAGTGGTTCTTTCTCGACCGGCCACTTTGACTAC heavy chain CDR3 (SEQ ID NO: 155)
- AACTCCAATATTGGAAATAATCTT light chain CDR1 (SEQ ID NO: 156)
- AACAATAAT light chain CDR2 (SEQ ID NO: 157)
- GCAGCAAGGGATAGCAGCCTGAGTGCTGTGGTG light chain CDR3 (SEQ ID NO: 158)
- SC2 antibody 3910 binds to Sino CoV2 SI (spike protein 1), NAC CoV2 SI, and Sino CoV2 RBD (Receptor Binding Domain).
- SC2 antibody 3915 binds to Sino CoV2 SI (spike protein 1), NAC CoV2 SI, Sino CoV2 RBD (Receptor Binding Domain), and NAC CoV2 Mosaic.
- the anti-SARS-CoV-2 antibodies 3910 (SEQ ID NO: 99 and 101), 3915 (SEQ ID NO: 109 and 111), 3945 (SEQ ID NO: 119 and 121), 3947 (SEQ ID NO: 129 and 131), 3969 (SEQ ID NO: 139 and 141), and 4083 (SEQ ID NO: 149 and 151) also include variable regions having amino acid sequences that have 99%, 95%, 90%, 80% or 70% sequence identity with one of the heavy chains from variable region SEQ ID NO: 99, 109, 119, 129, 139, or 149, and a light chain that has 99%, 95%, 90%, 80% or 70% sequence identity with one light chains from variable region SEQ ID NO: 101, 11, 121, 131, 141, or 151.
- CDRs from anti-SARS-CoV-2 antibodies 3910 (SEQ ID NO: 99 and 101), 3915 (SEQ ID NO: 109 and 111), 3945 (SEQ ID NO: 119 and 121), 3947 (SEQ ID NO: 129 and 131), 3969 (SEQ ID NO: 139 and 141), and 4083 (SEQ ID NO: 149 and 151) can be used to make CDR grafted antibodies known in the art.
- An anti-SARS-CoV-2 antibody can also include a variable region made from a nucleic acid encoding a heavy chain that has 99%, 95%, 90%, 80% or 70% sequence identity with one of the nucleic acids encoding a heavy chain (SEQ ID NO: 2, 6, 12, 16, 20, 24, 28, 32, 36, 100, 110, 120, 130, 140, or 150), and a nucleic acid encoding a light chain that has 99%, 95%, 90%, 80% or 70% sequence identity with one of the nucleic acids encoding a light chain (SEQ ID NO: 4, 8, 14, 18, 22, 26, 30, 34, 38, 102, 112, 122, 132, 142, or 152).
- An anti-SARS-CoV-2 antibody can also include a variable region made from a nucleic acid encoding a heavy chain that hybridizes under stringent hybridization conditions with one of the nucleic acids encoding one of the heavy chains (SEQ ID NO: 2, 6, 12, 16, 20, 24, 28, 32, 36, 100, 110, 120, 130, 140, or 150), and a nucleic acid encoding a light chain that hybridizes under stringent hybridization conditions with one of the nucleic acids encoding one of the light chains (SEQ ID NO: 4, 8, 14, 18, 22, 26, 30, 34, 38, 102, 112, 122, 132, 142, or 152).
- An anti-SARS-CoV-2 antibody can also include a variable region (e.g., starting from anti- SARS-CoV-2 variable regions (1) to (402)) made from a nucleic acid encoding a heavy chain that has 99%, 95%, 90%, 80% or 70% sequence identity with one of the heavy chain from variable regions 1-402 (odd numbered SEQ ID Nos), and a nucleic acid encoding a light chain that has 99%, 95%, 90%, 80% or 70% sequence identity with one of the light chain from variable region 1-402 (even numbered SEQ ID NOs).
- a variable region e.g., starting from anti- SARS-CoV-2 variable regions (1) to (402)
- a nucleic acid encoding a heavy chain that has 99%, 95%, 90%, 80% or 70% sequence identity with one of the heavy chain from variable regions 1-402 (odd numbered SEQ ID Nos)
- a nucleic acid encoding a light chain that has 99%, 95%
- An anti-SARS-CoV-2 antibody can also include a variable region made from a nucleic acid encoding a heavy chain that hybridizes under stringent hybridization conditions with one of the nucleic acids encoding one of the heavy chains from variable regions 903-1706 (odd numbered SEQ ID Nos), and a nucleic acid encoding a light chain that hybridizes under stringent hybridization conditions with one of the nucleic acids encoding one of the light chains from variable regions 903- (even numbered SEQ ID NOs).
- the CDRs for the light and heavy chains of the anti-SARS-CoV-2 variable regions 1-402 are known to a person of skill in the art. These CDRs and optionally FR amino acids from the corresponding light or heavy chain can be used to make CDR grafted antibodies as described below.
- the anti-SARS-CoV-2 antibodies disclosed herein can bind to SARS-CoV-2 Spike Trimer, SARS-CoV-2 Receptor Binding Domain (RBD), SARS-CoV-2 Membrane Protein (E), and/or SARS-CoV-2 Nucleocapsid. Antigen specificity for the anti-SARS-CoV-2 variable regions are shown in Table 2.
- antibodies that bind to SARS-CoV-2 RBD include, for example, anti-SARS-CoV-2 antibodies comprising the anti-SARS-CoV-2 variable region 2-6, 8-22, 24, 29- 34, 35-39, 41-42, 162, 165, 167, 172-173, 177-178, 180, 183-184, 186-187, 192-195, 288, 296, 298-299, 303-304, 313-316, 321-323, 326-328, 332, 334, 337-338, 344-345, 347, 350, 355-356, 358-360, 368-370, 378-380.
- antibodies that bind to SARS-CoV-2 Spike trimer include, for example, anti-SARS-CoV-2 antibodies comprising the anti-SARS-CoV-2 variable region 1-4, 7, 14-16, 19-20, 31, 37, 162, 171, 186.
- antibodies that bind to SARS- CoV-2 Membrane Protein include, for example, anti-SARS-CoV-2 antibodies comprising the anti- SARS-CoV-2 variable region 202-209, 218-219, 222-223, 227, 229-231, 242-245, 261, 280.
- antibodies that bind to SARS-CoV-2 Nucleocapsid include, for example, anti-SARS- CoV-2 antibodies comprising the anti-SARS-CoV-2 variable region 202-209, 214-215, 218-219, 221-223, 227, 229-231, 236, 242-243, 245, 261, 271, 280.
- any of the anti-SARS-CoV-2 antibodies described above can be made from a nucleic acid encoding a full-length antibody that lacks any introns, and so, is non-natural.
- the non-natural nucleic acids can include the combination of a variable region (e.g., anti-SARS-CoV-2 antibody variable regions 1-451) operably linked to a constant region (e.g., IgGl, IgG2, IgG3, or IgG4) that is non-natural for that variable region.
- a variable region e.g., anti-SARS-CoV-2 antibody variable regions 1-451
- a constant region e.g., IgGl, IgG2, IgG3, or IgG4
- the anti-SARS-CoV-2 antibodies also include amino acid sequences that are non-natural including the combination of a variable region (e.g., anti-SARS-CoV-2 antibody variable regions 1-451) operably linked to a constant region (e.g., IgGl, IgG2, IgG3, or IgG4) that is non-natural for that variable region.
- a variable region e.g., anti-SARS-CoV-2 antibody variable regions 1-451
- a constant region e.g., IgGl, IgG2, IgG3, or IgG4
- An anti-SARS-CoV-2 antibody can bind to SARS-CoV-2 with an affinity (Kd) of less than one picomolar.
- An anti-SARS-CoV-2 antibody can bind with an affinity of at least 1 pM, or at least 10 pM, or at least 100 pM.
- the anti-SARS-CoV-2 antibodies disclosed herein can also be used to make chimeric antigen receptors for arming T-cells treat infections from SARS-CoV-2.
- the antibodies can be formatted into a single chain structure recombinantly combined with appropriate transmembrane and signaling components to make a chimeric antigen receptor.
- the anti-SARS-CoV-2 antibodies disclosed herein can have neutralizing activity against SARS-CoV-2 in an in vitro cell infection model.
- the antibodies SC2 antibody 3417, SC2 antibody 3387, SC2 antibody 3396, and SC2 antibody 3705 neutralized SARS-CoV-2 and blocked the virus from infecting cells.
- the SC2 antibody 3387 was able to bind to spike proteins with the mutations D614G and E484K (Sweden-1 variant of European variant B-l), or D614G,V445I,H655Y,and E583D (England/Bristol variant of European variant B-l), or G485S (related to Australia-1 variant), or N501Y (South African variant Bl.l), or S494P, or V483K, or R683A, R685A, F817P, A892P, A899P, A942P, K986P, V987P.
- the ability to bind all of these variants shows the broad specificity of these anti-SARS-CoV-2 antibodies.
- the anti-SARS-CoV-2 antibodies described herein can be used in methods to neutralize SARS-CoV-2 and/or for treating CO VID-19 infection so as to reduce at least one symptom associated with COV ID- 19.
- Compositions comprising at least one isolated recombinant monoclonal antibody that binds specifically to SARS- CoV-2 virus and thereby neutralizes the virus are used in these methods.
- the anti-SARS-CoV-2 antibody can be administered prophylactically and/or can be administered to patients with COVID- 19 infections.
- the disclosure also relates to nucleic acids that encode, at least in part, the individual peptides, polypeptides, and proteins described herein.
- the nucleic acids may be natural, synthetic or a combination thereof.
- the nucleic acids may be RNA, mRNA, DNA or cDNA.
- Nucleic acids also include expression vectors, such as plasmids, or viral vectors, or linear vectors, or vectors that integrate into chromosomal DNA.
- Expression vectors can contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Such sequences are well known for a variety of cells. The origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria.
- the expression vector can be integrated into the host cell chromosome and then replicate with the host chromosome.
- vectors can be integrated into the chromosome of prokaryotic cells.
- Expression vectors also generally contain a selection gene, also termed a selectable marker. Selectable markers are well-known in the art for prokaryotic and eukaryotic cells, including host cells of the invention. Generally, the selection gene encodes a protein necessary for the survival or growth of transformed host cells grown in a selective culture medium. Host cells not transformed with the vector containing the selection gene will not survive in the culture medium.
- Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media, e.g., the gene encoding D-alanine racemase for Bacilli.
- an exemplary selection scheme utilizes a drug to arrest growth of a host cell. Those cells that are successfully transformed with a heterologous gene produce a protein conferring drug resistance and thus survive the selection regimen.
- Other selectable markers for use in bacterial or eukaryotic (including mammalian) systems are well-known in the art.
- EFla promoter An example of a promoter that is capable of expressing a transgene encoding an immune binding protein in a mammalian host cell is the EFla promoter.
- the native EFla promoter drives expression of the alpha subunit of the elongation factor- 1 complex, which is responsible for the enzymatic delivery of aminoacyl tRNAs to the ribosome.
- the EFla promoter has been extensively used in mammalian expression plasmids and has been shown to be effective in driving expression from transgenes cloned into a lentiviral vector. See, e.g., Milone et al., Mol. Ther. 17(8): 1453-1464 (2009), which is incorporated by reference in its entirety for all purposes.
- CMV immediate early cytomegalovirus
- This promoter sequence is a strong constitutive promoter sequence capable of driving high levels of expression of any polynucleotide sequence operatively linked thereto.
- Other constitutive promoter sequences may also be used, including, but not limited to the simian virus 40 (SV40) early promoter, mouse mammary tumor virus promoter (MMTV), human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter, MoMuLV promoter, phosphoglycerate kinase (PGK) promoter, MND promoter (a synthetic promoter that contains the U3 region of a modified MoMuLV LTR with myeloproliferative sarcoma virus enhancer, see, e.g., Li et al., J.
- an avian leukemia virus promoter an Epstein-Barr virus immediate early promoter, a Rous sarcoma virus promoter, as well as human gene promoters such as, but not limited to, the actin promoter, the myosin promoter, the elongation factor- la promoter, the hemoglobin promoter, and the creatine kinase promoter. Further, the invention is not limited to the use of constitutive promoters.
- inducible promoters are also contemplated herein.
- inducible promoters include, but are not limited to a metallothionine promoter, a glucocorticoid promoter, a progesterone promoter, a tetracycline promoter, a c-fos promoter, the T-REx system of ThermoFisher which places expression from the human cytomegalovirus immediate-early promoter under the control of tetracycline operator(s), and RheoSwitch promoters of Intrexon. Karzenowski, D. et al., BioTechiques 39: 191-196 (2005); Dai, X. et al., Protein Expr.
- Expression vectors typically have promoter elements, e.g., enhancers, to regulate the frequency of transcriptional initiation. Typically, these are located in the region 30-110 bp upstream of the start site, although a number of promoters have been shown to contain functional elements downstream of the start site as well. The spacing between promoter elements frequently is flexible, so that promoter function is preserved when elements are inverted or moved relative to one another. In the thymidine kinase (tk) promoter, the spacing between promoter elements can be increased to 50 bp apart before activity begins to decline. Depending on the promoter, it appears that individual elements can function either cooperatively or independently to activate transcription.
- promoter elements e.g., enhancers
- Control regions suitable for a bacterial host cell can be used in the expression vector. Suitable control regions for directing transcription of the nucleic acid constructs include, for example, the control regions obtained from the E. coli lac operon, Streptomyces coelicolor agarase gene (dagA), Bacillus subtilis levansucrase gene (sacB), Bacillus licheniformis alpha-amylase gene (amyL), Bacillus stearothermophilus maltogenic amylase gene (amyM), Bacillus amyloliquefaciens alpha-amylase gene (amyQ), Bacillus licheniformis penicillinase gene (penP), Bacillus subtilis xylA and xylB genes, and the prokaryotic beta-lactamase gene, the tac promoter, or the T7 promoter.
- dagA Streptomyces coelicolor agarase gene
- sacB Bacillus subtilis le
- control regions for filamentous fungal host cells include control regions obtained from the genes for Aspergillus oryzae TAKA amylase, Rhizomucor miehei aspartic proteinase, Aspergillus niger neutral alpha-amylase, Aspergillus niger acid stable alphaamylase, Aspergillus niger ox Aspergillus awamori glucoamylase (glaA), Rhizomucor miehei lipase, Aspergillus oryzae alkaline protease, Aspergillus oryzae triose phosphate isomerase, Aspergillus nidulans acetamidase, and Fusarium oxysporum trypsin-like protease (WO 96/00787), as well as the NA2-tpi promoter (a hybrid of the promoters from the genes for Aspergillus niger neutral alpha-amylase
- Exemplary yeast cell control regions can be from the genes for Saccharomyces cerevisiae enolase (ENO-1), Saccharomyces cerevisiae galactokinase (GALI), Saccharomyces cerevisiae alcohol dehydrogenase/glyceraldehyde-3- phosphate dehydrogenase (ADH2/GAP), and Saccharomyces cerevisiae 3 -phosphoglycerate kinase.
- Exemplary control regions for insect cells include, among others, those based on polyhedron, PCNA, OplE2, OplEl, Drosophila metallothionein, and Drosophila actin 5C.
- insect cell promoters can be used with Baculoviral vectors.
- Exemplary control regions for plant cells include, among others, those based on cauliflower mosaic virus (CaMV) 35S, polyubiquitin gene (PvUbil and PvUbi2), rice (Oryza saliva) actin 1 (OsActl) and actin 2 (OsAct2) control regions, the maize ubiquitin 1 (ZmUbil) control region, and multiple rice ubiquitin (RUBQ1, RUBQ2, rubi3) control regions.
- CaMV cauliflower mosaic virus
- PvUbil and PvUbi2 polyubiquitin gene
- rice Oryza saliva
- actin 1 OsActl
- actin 2 actin 2
- ZmUbil maize ubiquitin 1
- RUBQ2, rubi3 multiple rice ubiquitin
- the expression vector can contain one or more selectable markers, which permit selection of transformed cells.
- a selectable marker is a gene the product of which provides for biocide or viral resistance, resistance to heavy metals, prototrophy to auxotrophs, and the like.
- Examples of bacterial selectable markers are the dal genes from Bacillus subtilis or Bacillus Ucheniformis. or markers, which confer antibiotic resistance such as ampicillin, kanamycin, chloramphenicol (Example 1) or tetracycline resistance.
- Suitable markers for yeast host cells are ADE2, HIS3, LEU2, LYS2, MET3, TRP1, and URA3.
- Selectable markers for use in a filamentous fungal host cell include, but are not limited to, amdS (acetamidase), argB (ornithine carbamoyltransferase), bar (phosphinothricin acetyltransferase), hph (hygromycin phosphotransferase), niaD (nitrate reductase), pyrG (orotidine-5'-phosphate decarboxylase), sC (sulfate adenyltransferase), and trpC (anthranilate synthase), as well as equivalents thereof.
- amdS acetamidase
- argB ornithine carbamoyltransferase
- bar phosphinothricin acetyltransferase
- hph hygromycin phosphotransferase
- niaD nitrate reductase
- Embodiments for use in an Aspergillus cell include the amdS and pyrG genes of Aspergillus nidulans ox Aspergillus oryzae and the bar gene of Streptomyces hygroscopicus.
- the polynucleotides described herein also include polynucleotides including nucleotide sequences that are substantially equivalent to the polynucleotides described herein.
- Polynucleotides according to the invention can have at least about 80%, more typically at least about 90%, and even more typically at least about 95%, sequence identity to a polynucleotide of the invention.
- the invention also provides the complement of the polynucleotides including a nucleotide sequence that has at least about 80%, more typically at least about 90%, and even more typically at least about 95%, sequence identity to a polynucleotide encoding a polypeptide recited above.
- the polynucleotide can be DNA (genomic, cDNA, amplified, or synthetic) or RNA. Methods and algorithms for obtaining such polynucleotides are well known to those of skill in the art and can include, for example, methods for determining hybridization conditions which can routinely isolate polynucleotides of the desired sequence identities.
- Nucleic acids which encode protein analogs or variants in accordance with those described herein may be produced using site directed mutagenesis or PCR amplification in which the primer(s) have the desired point mutations.
- site directed mutagenesis or PCR amplification in which the primer(s) have the desired point mutations.
- suitable mutagenesis techniques see Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989) and/or Current Protocols in Molecular Biology, Ausubel et al., eds, Green Publishers Inc. and Wiley and Sons, N.Y (1994), each of which is incorporated by reference in its entirety for all purposes.
- Amino acid “substitutions” for creating variants can be preferably the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, z.e., conservative amino acid replacements. Amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved.
- nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine;
- polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine;
- positively charged (basic) amino acids include arginine, lysine, and histidine; and negatively charged (acidic) amino acids include aspartic acid and glutamic acid.
- nucleic acids described herein can be linked to another nucleic acid so as to be expressed under control of a suitable promoter.
- the nucleic acid can be also linked to, in order to attain efficient transcription of the nucleic acid, other regulatory elements that cooperate with a promoter or a transcription initiation site, for example, a nucleic acid comprising an enhancer sequence, a polyA site, or a terminator sequence.
- a gene that can be a marker for confirming expression of the nucleic acid e.g. a drug resistance gene, a gene encoding a reporter enzyme, or a gene encoding a fluorescent protein
- a marker for confirming expression of the nucleic acid e.g. a drug resistance gene, a gene encoding a reporter enzyme, or a gene encoding a fluorescent protein
- the nucleic acid described herein When the nucleic acid described herein is introduced into a cell ex vivo, the nucleic acid of may be combined with a substance that promotes transference of a nucleic acid into a cell, for example, a reagent for introducing a nucleic acid such as a liposome or a cationic lipid, in addition to the aforementioned excipients.
- a vector carrying the nucleic acid can also be useful.
- a composition in a form suitable for administration to a living body which contains the nucleic acid of the present invention carried by a suitable vector is suitable for in vivo gene therapy.
- Nucleic acids encoding an immune binding protein described herein can be cloned into an appropriate expression vector for expression of immune binding protein in a host cell.
- Host cells include, for example, bacterial, fungi, or mammalian host cells.
- the host cell can be a bacterium including, for example, Bacillus, such as B. lichenformis or B. subliHs: Pantoea, such as P. cilrea: Pseudomonas, such as P. alcaligenes,' Streptomyces, such as S. lividans or S. rubiginosus,' Escherichia, such as E. coli ⁇ Enter obacter, Streptococcus,' Archaea, such as Methanosarcina mazer, or Corynebacterium, such as C. glutamicum.
- the host cells can be fungi cells, including, but not limited to, fungi of the genera Saccharomyces, Klyuveromyces, Candida, Pichia, Debaromyces, Hansenula, Yarrowia, Zygosaccharomyces, or Schizosaccharomyces .
- the host cell is a fungi, including, among others, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Kluyveromyces lactis, Kluyveromyces marxianus, Aspergillus terreus, Aspergillus niger, Pichia pastoris, Rhizopus arrhizus, Rhizobus oryzae, Yarrowia lipolytica, and the like.
- the eukaryotic cells can be algal, including but not limited to algae of the genera Chlorella, Chlamydomonas, Scenedesmus, Isochrysis, Dunaliella, Tetraselmis, Nannochloropsis, or Prototheca.
- the algae can be a green algae, red algae, glaucophytes, chlorarachniophytes, euglenids, chromista, or dinoflagellates.
- the eukaryotic cells can be mammalian cells, such as mouse, rat, rabbit, hamster, porcine, bovine, feline, or canine.
- the mammalian cells can be cells of primates, including but not limited to, monkeys, chimpanzees, gorillas, and humans.
- the mammalians cells can be mouse cells, as mice routinely function as a model for other mammals, most particularly for humans (see, e.g, Hanna, J. et al., Science 318: 1920-23, 2007; Holtzman, D.M. et al., J Clin Invest. 103(6):R15-R21, 1999; Warren, R.S. et al., J Clin Invest.
- Animal cells include, for example, fibroblasts, epithelial cells (e.g., renal, mammary, prostate, lung), keratinocytes, hepatocytes, adipocytes, endothelial cells, and hematopoietic cells.
- the animal cells are adult cells (e.g., terminally differentiated, dividing or non-dividing) or embryonic cells (e.g., blastocyst cells, etc.) or stem cells.
- the animal cell can be a cell line derived from an animal or other source, such as a Chinese hamster ovary cell line (CHO cell), or murine myeloma cell lines (NS0, Sp2/0), or human cell lines including, for example, HEK293, HT-1080, or PER.C6.
- CHO cell Chinese hamster ovary cell line
- NS0, Sp2/0 murine myeloma cell lines
- human cell lines including, for example, HEK293, HT-1080, or PER.C6.
- the mammalian cell can be a cell found in the circulatory system of a mammal, including humans.
- Exemplary circulatory system cells include, among others, red blood cells, platelets, plasma cells, T-cells, natural killer cells, B-cells, macrophages, neutrophils, or the like, and precursor cells of the same. As a group, these cells are defined to be circulating eukaryotic cells of the invention.
- the mammalian cells can be derived from any of these circulating eukaryotic cells.
- the immiuner binding proteins described herein may be used with any of these circulating cells or cells derived from the circulating cells.
- the mammalian cell can be a T-cell or T-cell precursor or progenitor cell.
- the mammalian cell can be a helper T-cell, a cytotoxic T-cell, a memory T-cell, a regulatory T-cell, a natural killer T-cell, a mucosal associated invariant T-cell, a gamma delta T cell, or a precursor or progenitor cell to the aforementioned.
- the mammalian cell can be a natural killer cell, or a precursor or progenitor cell to the natural killer cell.
- the mammalian cell can be a B-cell, or a plasma cell, or a B-cell precursor or progenitor cell.
- the mammalian cell can be a neutrophil or a neutrophil precursor or progenitor cell.
- the mammalian cell can be a megakaryocyte or a precursor or progenitor cell to the megakaryocyte.
- the mammalian cell can be a macrophage or a precursor or progenitor cell to a macrophage.
- a source of cells can be obtained from a subject.
- the subject may be any living organism. Examples of subjects include humans, dogs, cats, mice, rats, and transgenic species thereof.
- T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. Any number of T cell lines available in the art, may be used.
- T cells can be obtained from a unit of blood collected from a subj ect using any number of techniques known to the skilled artisan, such as Ficoll separation. Cells from the circulating blood of an individual can be obtained by apheresis.
- the apheresis product typically contains lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and platelets.
- the cells collected by apheresis may be washed to remove the plasma fraction and to place the cells in an appropriate buffer or media for subsequent processing steps.
- the cells can be washed with phosphate buffered saline (PBS).
- the wash solution lacks calcium and may lack magnesium or may lack many if not all divalent cations. Initial activation steps in the absence of calcium can lead to magnified activation.
- Plant cells can be cells of monocotyledonous or dicotyledonous plants, including, but not limited to, alfalfa, almonds, asparagus, avocado, banana, barley, bean, blackberry, brassicas, broccoli, cabbage, canola, carrot, cauliflower, celery, cherry, chicory, citrus, coffee, cotton, cucumber, eucalyptus, hemp, lettuce, lentil, maize, mango, melon, oat, papaya, pea, peanut, pineapple, plum, potato (including sweet potatoes), pumpkin, radish, rapeseed, raspberry, rice, rye, sorghum, soybean, spinach, strawberry, sugar beet, sugarcane, sunflower, tobacco, tomato, turnip, wheat, zucchini, and other fruiting vegetables (e.g.
- plants refers to all physical parts of a plant, including seeds, seedlings, saplings, roots, tubers, stems, stalks, foliage and fruits.
- CDR grafted forms of antibodies are chimeric immunoglobins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')2 or other antigen-binding subsequences of antibodies) which contain CDR sequences derived from one immunoglobulin grafted into the framework sequences of a second immunoglobulin.
- CDR grafted antibodies include immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient antibody are replaced by residues from a CDR of another antibody (donor antibody) having the desired specificity, affinity and capacity.
- CDR complementary determining region
- donor antibody having the desired specificity, affinity and capacity.
- Fv framework residues of the recipient antibody are replaced by corresponding residues from the donor antibody.
- CDR grafted antibodies may also comprise residues which are found neither in the recipient antibody nor in the donor CDR or framework sequences.
- the CDR grafted antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a donor antibody and all or substantially all of the FR regions are those of a recipient antibody consensus sequence.
- the CDR grafted antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a recipient antibody [Jones et al., Nature, 321 :522-525 (1986); Riechmann et al., Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992), all of which are incorporated by reference in their entirety for all purposes],
- Fc immunoglobulin constant region
- Humanization is one type of CDR grafting to make a chimeric antibody.
- Methods for humanizing non-human antibodies are well known in the art.
- humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non- human amino acid residues are often referred to as "import" residues, which are typically taken from an "import” variable domain.
- Humanization can be essentially performed following the method of Winter and co-workers [Jones et al., Nature, 321 :522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239: 1534-1536 (1988), all of which are incorporated by reference in their entirety for all purposes], by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such "humanized" antibodies are chimeric antibodies (U.S. Pat. No.
- humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
- bispecific antibodies may bind to two different epitopes of SARS-CoV-2.
- an anti-SARS-CoV-2 arm may be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g., CD2 or CD3), or Fc receptors for IgG (Fc gamma Receptor), such as FcgRI (CD64), FcgRII (CD32) and FcgRIII (CD 16).
- Bispecific antibodies may also be used to localize cytotoxic agents.
- bispecific antibodies possess an SARS-CoV-2-binding arm and an arm which binds the cytotoxic agent (e.g., saporin, anti-interferon-alpha, vinca alkaloid, ricin A chain, methotrexate or radioactive isotope hapten).
- cytotoxic agent e.g., saporin, anti-interferon-alpha, vinca alkaloid, ricin A chain, methotrexate or radioactive isotope hapten.
- Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g., F(ab')2 bispecific antibodies).
- the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture.
- the preferred interface comprises at least a part of the CH3 domain of an antibody constant domain.
- one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g., tyrosine or tryptophan).
- Compensatory "cavities" of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g., alanine or threonine).
- Bispecific antibodies include cross-linked or "heteroconjugate" antibodies.
- one of the antibodies in the heteroconjugate can be coupled to avidin, the other to biotin.
- Heteroconjugate antibodies may be made using any convenient cross-linking methods. Suitable cross-linking agents are well known in the art, and are disclosed in U.S. Pat. No. 4,676,980, which is incorporated by reference in its entirety for all purposes, along with a number of cross-linking techniques.
- bispecific antibodies can be prepared using chemical linkage.
- Brennan et al. Science 229:81 (1985) (which is incorporated by reference in its entirety for all purposes) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab')2 fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation.
- the Fab' fragments generated are then converted to thionitrobenzoate (TNB) derivatives.
- Fab'-TNB derivatives is then reconverted to the Fab'-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab'-TNB derivative to form the bispecific antibody.
- the bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.
- Fab'-SH fragments directly recovered from E. coli can be chemically coupled in vitro to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175:217 225 (1992) (which is incorporated by reference in its entirety for all purposes).
- bispecific antibodies have been produced using leucine zippers.
- the leucine zipper peptides from the Fos and Jun proteins were linked to the Fab' portions of two different antibodies by gene fusion.
- the antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers.
- the fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites.
- VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites.
- sFv single-chain Fv
- the bispecific antibody may be a "linear antibody” produced as described in Zapata et al. Protein Eng. 8(10): 1057 1062 (1995) which is incorporated by reference in its entirety for all purposes.
- Antibodies with more than two valencies are contemplated.
- trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991) which is incorporated by reference in its entirety for all purposes.
- An anti-SARS-CoV-2 antibody can include a moiety that extends a half-life (T1/2) or/and the duration of action of the antibody.
- the moiety can extend the circulation T 1/2, blood T 1/2, plasma T1/2, serum T1/2, terminal T1/2, biological T1/2, elimination T1/2 or functional T1/2, or any combination thereof, of the antibody.
- An anti-SARS-CoV-2 antibody may be modified by a single moiety.
- an anti- SARS-CoV-2 antibody may be modified by two or more substantially similar or identical moieties or two or more moieties of the same type.
- An anti-SARS-CoV-2 antibody may include two or more moieties of different types, or two or more different types of moieties.
- Two or more anti-SARS- CoV-2 antibodies can also be attached to one moiety. The attachment between the anti-SARS- CoV-2 antibody and the moiety can be covalent or noncovalent.
- a polypeptide moiety can be recombinantly fused to the N-terminus or the C-terminus of the heavy chain or the light chain of an anti-SARS-CoV-2 antibody, optionally via a linker.
- the linker may contain about 4-30 amino acid residues.
- the linker may contain from about 6 or 8 amino acid residues to about 20 amino acid residues, or from about 6 or 8 amino acid residues to about 15 amino acid residues.
- a protracting moiety can be human serum albumin (HSA) or a portion thereof (e.g., domain III) that binds to the neonatal Fc receptor (FcRn).
- HSA or FcRn-binding portion thereof can optionally have one or more mutations that confer a beneficial property or effect.
- the HSA or FcRn-binding portion thereof has one or more mutations that enhance pH-dependent HSA binding to FcRn or/and increase HSA half-life, such as K573P or/and E505G/V547A.
- a protracting moiety can be an unstructured polypeptide.
- a protracting moiety can be a carboxy-terminal peptide (CTP) derived from the P-subunit of human chorionic gonadotropin (hCG).
- CTP carboxy-terminal peptide
- hCG human chorionic gonadotropin
- the fourth, fifth, seventh and eight serine residues of the 34-aa CTP of hCG-P typically are attached to O-glycans terminating with a sialic acid residue.
- a protracting moiety can be 1, 2, 3, 4, 5 or more moi eties of a synthetic polymer.
- the synthetic polymer can be biodegradable or non-biodegradable.
- Biodegradable polymers useful as protracting moieties include, but are not limited to, poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) and poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA).
- Non-biodegradable polymers useful as protracting moieties include without limitation polyethylene glycol) (PEG), polyglycerol, poly(A-(2-hydroxypropyl)methacrylamide) (PHPMA), polyoxazolines and poly(A-vinylpyrrolidone) (PVP).
- a synthetic polymer can be polyethylene glycol (PEG). PEGylation can be done by chemical or enzymatic, site-specific coupling or by random coupling.
- the protracting moieties can also include but are not limited to water soluble polymers.
- 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, proly propylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof.
- PEG polyethylene glycol
- 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 a therapy under defined conditions, etc.
- the individual mass (e.g., average molecular weight), or the total mass, of the one or more synthetic polymer moieties can be about 10-50, 10-20, 20-30, 30-40 or 40-50 kDa, or about 10, 20, 30, 40 or 50 kDa.
- the individual mass (e.g., average MW), or the total mass, of the one or more synthetic polymer moieties also can be greater than about 50 kDa, such as about 50-100, 50-60, 60- 70, 70-80, 80-90 or 90-100 kDa, or about 60, 70, 80, 90 or 100 kDa.
- the mass (e.g., average MW) of an individual synthetic polymer moiety can be less than about 10 kDa, such as about 1-5 or 5-10 kDa, or about 5 kDa.
- the individual mass (e.g., average MW), or the total mass, of the one or more synthetic polymer (e.g., PEG) moieties can be about 20 or 40 kDa.
- compositions [138] Antibodies specifically binding SARS-CoV-2 identified herein, as well as other immune binding proteins identified by the screening assays disclosed hereinbefore, can be administered for the treatment of various disorders in the form of pharmaceutical compositions.
- compositions generally are prepared according to current good manufacturing practice (GMP), as recommended or required by, e.g., the Federal Food, Drug, and Cosmetic Act ⁇ 501(a)(2)(B) and the International Conference on Harmonisation Q7 Guideline.
- GMP current good manufacturing practice
- compositions/formulations can be prepared in sterile form.
- pharmaceutical compositions/formulations for parenteral administration by injection or infusion generally are sterile.
- Sterile pharmaceutical compositions/formulations are compounded or manufactured according to pharmaceutical-grade sterilization standards known to those of skill in the art, such as those disclosed in or required by the United States Pharmacopeia Chapters 797, 1072 and 1211, and 21 Code of Federal Regulations 211.
- compositions and carriers include pharmaceutically acceptable substances, materials and vehicles.
- types of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersing agents, disintegration agents, emulsifying agents, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pH adjusters, absorption-delaying agents, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweetening agents, flavoring agents, coloring agents, encapsulating materials and coating materials.
- the use of such excipients in pharmaceutical formulations is known in the art.
- oils e.g., vegetable oils such as olive oil and sesame oil
- aqueous solvents e.g., saline, buffered saline (e.g., phosphate-buffered saline [PBS]) and isotonic solutions (e.g., Ringer’s solution) ⁇
- organic solvents e.g., dimethyl sulfoxide [DMSO] and alcohols [e.g., ethanol, glycerol and propylene glycol]
- any conventional excipient or carrier is incompatible with an anti-SARS-CoV2 antibody or a fragment thereof
- the disclosure encompasses the use of conventional excipients and carriers in formulations containing an anti-SARS-CoV2 antibody or a fragment thereof. See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania) (2005); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Co.
- a pharmaceutical composition comprising an anti- SARS-CoV2 antibody or a fragment thereof include without limitation oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intraperitoneal, intramedullary, intrathecal and topical), intracavitary, and topical (including dermal/epicutaneous, transdermal, mucosal, transmucosal, intranasal [e.g., by nasal spray or drop], intraocular [e.g., by eye drop], pulmonary [e.g., by oral or nasal inhalation], buccal, sublingual, rectal [e.g., by suppository], and vaginal [e.g., by suppository]).
- parenteral including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intraperitoneal, intramedullary, intrathecal and topical
- intracavitary and topical
- topical including dermal/
- Topical formulations can be designed to produce a local or systemic therapeutic effect.
- an anti-SARS-CoV2 antibody or a fragment thereof is administered parenterally (e.g., intravenously, subcutaneously, intramuscularly or intraperitoneally) by injection (e.g., as a bolus) or by infusion over a period of time.
- Excipients and carriers that can be used to prepare parenteral formulations include without limitation solvents (e.g., aqueous solvents such as water, saline, physiological saline, buffered saline [e.g., phosphate-buffered saline], balanced salt solutions [e.g., Ringer’s BSS] and aqueous dextrose solutions), isotonic/iso-osmotic agents (e.g., salts [e.g., NaCl, KC1 and CaC12] and sugars [e.g., sucrose]), buffering agents and pH adjusters (e.g., sodium dihydrogen phosphate [monobasic sodium phosphate]/di sodium hydrogen phosphate [dibasic sodium phosphate], citric acid/sodium citrate and L-histidine/L-histidine HC1), and emulsifiers (e.g., non-ionic surfactants such as polysorbates [
- the excipients can optionally include one or more substances that increase protein stability, increase protein solubility, inhibit protein aggregation or reduce solution viscosity, or any combination or all thereof.
- substances include without limitation hydrophilic amino acids (e.g., arginine and histidine), polyols (e.g., myo-inositol, mannitol and sorbitol), saccharides ⁇ e.g., glucose (including D-glucose [dextrose]), lactose, sucrose and trehalose ⁇ , osmolytes (e.g., trehalose, taurine, amino acids [e.g., glycine, sarcosine, alanine, proline, serine, L- alanine and y-aminobutyric acid], and betaines [e.g., trimethylglycine and trimethylamine N- oxide]), and non-ionic surfactants ⁇ e.g., alky
- a sterile solution or suspension of an anti-SARS-CoV2 antibody in an aqueous solvent containing one or more excipients can be prepared beforehand and can be provided in, e.g., a pre-filled syringe.
- an anti-SARS-CoV2 antibody can be dissolved or suspended in an aqueous solvent that can optionally contain one or more excipients prior to lyophilization (freeze-drying).
- the lyophilized anti-SARS-CoV2 antibody stored in a suitable container can be reconstituted with, e.g., sterile water that can optionally contain one or more excipients.
- a suitable container e.g., a vial
- the solution or suspension of the reconstituted anti-SARS-CoV2 antibody can be added to and diluted in an infusion bag containing, e.g., sterile saline (e.g., about 0.9% NaCl).
- Excipients that enhance transmucosal penetration of smaller proteins include without limitation cyclodextrins, alky saccharides (e.g., alkyl glycosides and alkyl maltosides [e.g., tetradecylmaltoside]), and bile acids (e.g., cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, glycodeoxycholic acid, chenodeoxycholic acid and dehydrocholic acid).
- alky saccharides e.g., alkyl glycosides and alkyl maltosides [e.g., tetradecylmaltoside]
- bile acids e.g., cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, glycodeoxycholic acid, chenodeoxycholic acid and dehydrocholic acid.
- Excipients that enhance transepithelial or transdermal penetration of smaller proteins include without limitation chemical penetration enhancers (CPEs, including fatty acids [e.g., oleic acid]), cell-penetrating peptides ⁇ CPPs, including arginine-rich CPPs [e.g., polyarginines such as R6-R11 (e.g., R6 and R9) and TAT -related CPPs such as TAT(49-57)] and amphipathic CPPs [e.g., Pep-1 and penetratin] ⁇ , and skin-penetrating peptides (SPPs, such as the skin-penetrating and cellentering [SPACE] peptide).
- CPEs chemical penetration enhancers
- fatty acids e.g., oleic acid
- CPPs cell-penetrating peptides
- arginine-rich CPPs e.g., polyarginines such as R6-R11 (
- Transdermal penetration of smaller proteins can be further enhanced by use of a physical enhancement technique, such as iontophoresis, cavitational or non-cavitational ultrasound, electroporation, thermal ablation, radio frequency, microdermabrasion, microneedles or jet injection.
- a physical enhancement technique such as iontophoresis, cavitational or non-cavitational ultrasound, electroporation, thermal ablation, radio frequency, microdermabrasion, microneedles or jet injection.
- US 2007/0269379 provides an extensive list of CPEs. F. Milletti, Drug Discov. Today, 17:850-860 (2012) is a review of CPPs. R. Ruan et al., Ther. Deliv., 7:89-100 (2016) discuss CPPs and SPPs for transdermal delivery of macromolecules, and M. Prausnitz and R. Langer, Nat. Biotechnol., 26: 1261-1268 (2008) discuss a variety of transdermal drug-delivery methods.
- An anti-SARS-CoV-2 antibody can be delivered from a sustained-release composition.
- sustained-release composition encompasses sustained-release, prolonged- release, extended-release, slow-release and controlled-release compositions, systems and devices. Protein delivery systems are discussed in, e.g., Banga (supra).
- a sustained-release composition can deliver a therapeutically effective amount of an anti-SARS-CoV2 antibody over a prolonged time period.
- a sustained-release composition delivers an anti-SARS-CoV2 antibody over a period of at least about 3 days, 1 week, 2 weeks, 3 weeks, 1 month (4 weeks), 6 weeks, 2 months, 3 months or longer.
- a sustained-release composition can be administered, e.g., parenterally (e.g., intravenously, subcutaneously or intramuscularly).
- a sustained-release composition of a protein can be in the form of, e.g., a particulate system, a lipid or oily composition, or an implant.
- Particulate systems include without limitation nanoparticles, nanospheres, nanocapsules, microparticles, microspheres and microcapsules. Nanoparticulate systems generally have a diameter or an equivalent dimension smaller than about 1 pm. In certain embodiments, a nanoparticle, nanosphere or nanocapsule has a diameter or an equivalent dimension of no more than about 500, 400 or 300 nm, or no more than about 200, 150 or 100 nm.
- a microparticle, microsphere or microcapsule has a diameter or an equivalent dimension of about 1-200, 100-200 or 50-150 pm, or about 1-100, 1-50 or 50-100 pm.
- a nano- or microcapsule typically contains the therapeutic agent in the central core, while the therapeutic agent typically is dispersed throughout a nano- or microparticle or sphere.
- a nanoparticulate system is administered intravenously, while a microparticulate system is administered subcutaneously or intramuscularly.
- a sustained-release particulate system or implant is made of a biodegradable polymer or/and a hydrogel.
- the biodegradable polymer comprises lactic acid or/and glycolic acid [e.g., an L-lactic acid-based copolymer, such as poly(L- lactide-co-glycolide) or poly(L-lactic acid-co-D,L-2-hydroxyoctanoic acid)].
- Non-limiting examples of polymers of which a hydrogel can be composed include polyvinyl alcohol, acrylate polymers (e.g., sodium polyacrylate), and other homopolymers and copolymers having a relatively large number of hydrophilic groups (e.g., hydroxyl or/and carboxylate groups).
- the biodegradable polymer of the particulate system or implant can be selected so that the polymer substantially completely degrades around the time the period of treatment is expected to end, and so that the byproducts of the polymer’s degradation, like the polymer, are biocompatible.
- a sustained-release composition of a protein can be composed of a non- biodegradable polymer.
- non-biodegradable polymers include without limitation poloxamers (e.g., poloxamer 407).
- Sustained-release compositions of a protein can be composed of other natural or synthetic substances or materials, such as hydroxyapatite.
- Sustained-release lipid or oily compositions of a protein can be in the form of, e.g., liposomes, micelles (e.g., those composed of biodegradable natural or/and synthetic polymers, such as lactosomes), and emulsions in an oil.
- a sustained-release composition can be formulated or designed as a depot, which can be injected or implanted, e.g., subcutaneously or intramuscularly.
- a depot can be in the form of, e.g., a polymeric particulate system, a polymeric implant, or a lipid or oily composition.
- a depot formulation can comprise a mixture of a protein and, e.g., a biodegradable polymer [e.g., poly(lactide-co-glycolide)] or a semi-biodegradable polymer (e.g., a block copolymer of lactic acid and PEG) in a biocompatible solvent system, whether or not such a mixture forms a particulate system or implant.
- a pharmaceutical composition can be presented in unit dosage form as a single dose wherein all active and inactive ingredients are combined in a suitable system, and components do not need to be mixed to form the composition to be administered.
- the unit dosage form generally contains an effective dose of the therapeutic agent.
- a representative example of a unit dosage form is a single-use pen comprising a pre-filled syringe, a needle and a needle cover for parenteral (e.g., intravenous, subcutaneous or intramuscular) injection of the therapeutic agent.
- a pharmaceutical composition can be presented as a kit in which the therapeutic agent, excipients and carriers (e.g., solvents) are provided in two or more separate containers (e.g., ampules, vials, tubes, bottles or syringes) and need to be combined to form the composition to be administered.
- the kit can contain instructions for storing, preparing and administering the composition (e.g., a solution to be injected intravenously or subcutaneously).
- Suitable host cells for making immune binding proteins recombinantly include higher eukaryote cells described herein, including vertebrate host cells. Propagation of vertebrate cells in culture (tissue culture) has become a routine procedure. Examples of useful mammalian host cell lines are monkey kidney CV 1 line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture. Graham et al., J. Gen Virol.
- baby hamster kidney cells BEK, ATCC CCL 10
- Chinese hamster ovary cells/-DHFR CHO, Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); mouse sertoli cells (TM4, Mather. Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat liver cells (BRL 3 A, ATCC CRL 1442); human lung cells (W138.
- BEK baby hamster kidney cells
- Chinese hamster ovary cells/-DHFR CHO, Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)
- mouse sertoli cells TM4, Mather. Biol. Reprod. 23:243-251 (1980)
- ATCC CCL 75 human liver cells (Hep G2, HB 8065); mouse mammary tumor (MMT 060562. ATCC CCL51); TRI cells (Mather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982)); MRC 5 cells; FS4 cells: and a human hepatoma line (Hep G2).
- the host cells used to produce the immune binding proteins described herein may be cultured in a variety of media.
- Commercially available media such as Ham's F10 (Sigma), Minimal Essential Medium ((MEM), (Sigma), RPMI-1640 (Sigma), and Dulbecco's Modified Eagle's Medium ((DMEM). Sigma) are suitable for culturing the host cells.
- any of these media may be supplemented as necessary with hormones and/or other growth factors (such as insulin, transferrin, or epidermal growth factor), salts (such as sodium chloride, calcium, magnesium, and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics (such as GENTAMYCINTM drug), trace elements (defined as inorganic compounds usually present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Any other necessary supplements may also be included at appropriate concentrations that would be known to those skilled in the art.
- the culture conditions such as temperature, pH, and the like, are those previously used with the host cell selected for expression, and will be apparent to the ordinarily skilled artisan.
- Anti-SARS-CoV-2 antibodies made recombinantly as described above will typically have altered glycosylation from naturally occurring human antibodies. For example, if the anti-SARS- CoV-2 antibodies are made in CHO cells, the glycosylation on the full-length antibodies will be non-human, and can change biochemical properties of the antibodies and change the half-life of the antibodies.
- the nucleic acids encoding the anti-SARS-CoV-2 antibodies and used to recombinantly produce the anti-SARS-CoV-2 antibodies can be codon optimized for the host cell used to recombinantly make the antibodies.
- the codon optimization can be done on at least one or more codons of the nucleic acid to make a non-naturally occurring nucleic acid. Methods for codon optimizing nucleic acids for recombinant production are well known in the art.
- the methods herein include administering to the subject one or more additional therapeutic agents in combination with an antibody or other immune binding proteins obtained (e.g., anti-SARS-CoV-2 antibody).
- an antibody or other immune binding proteins obtained e.g., anti-SARS-CoV-2 antibody.
- the expression “in combination with” means that the additional therapeutic agents is/are administered before, after, or concurrent with the pharmaceutical composition comprising the immune binding proteins described herein (e.g., anti- SARS-CoV-2 antibody).
- the term “in combination with” also includes sequential or concomitant administration of the immune binding protein described herein and a second therapeutic agent (which could be a different immune binding protein described herein).
- Combination therapies may include an anti-SARS-CoV antibody and any additional therapeutic agent that may be advantageously combined with an antibody described herein, or with a biologically active fragment of an antibody described herein.
- a second or third therapeutic agent may be employed to aid in reducing the viral load in the lungs, such as an antiviral, for example, Remdesivir (Veklury), ribavirin, nucleoside analogs, etc.
- the antibodies may also be used in conjunction with other therapies, including a toxoid, a vaccine specific for SARS-CoV-2, a second antibody specific for SARS-CoV-2, or an antibody specific for another SARS-CoV-2 antigen.
- the additional therapeutic agent can also be one that ameliorates certain symptoms of SARS-CoV-2, such as, for example, cytokine storm, fever, inflammation, etc.
- Additional therapeutic agents can include, for example, dexamethasone, other corticosteroids, etc.
- the immune binding proteins described herein can be used in therapies for infectious diseases, cancer, allergies, and autoimmune diseases.
- the methods described herein can be used to make repertoires of immune binding proteins from subjects that have been challenged/infected with an infectious agent.
- the immune binding proteins described herein can be used in therapies to treat subjects infected with an infectious agent such as coronavirus (e.g., SARS-CoV-2).
- an infectious agent such as coronavirus (e.g., SARS-CoV-2).
- Addition of the exogenous immune binding protein e.g., anti -SARS-CoV-2 antibody helps the subject’s body accelerate its own immune response to a pathogen, in effect “transplanting” the immunity from one individual to another.
- the immune binding proteins described herein can be used prophylactically to provide protection to those individuals who are particularly susceptible to a disease or particularly susceptible to bad outcomes from a disease.
- the immune binding proteins described herein can also be used in diagnostic applications.
- the immune binding proteins described herein can provide information on a subject’s response to a therapy.
- the immune binding proteins described herein can provide information on a subject’s response to an antibody therapy, small molecule drug therapy, biologic therapy, or cellular immunotherapy.
- the immune binding proteins can be obtained from a subject that neutralized an infectious agent and overcame the infection.
- the infectious agent can be a bacterial strain of Staphylococci, Streptococcus, Escherichia coli, Pseudomonas, or Salmonella.
- the infectious agent canbe a Staphylococcus aureus, Neisseria gonorrhoeae, Streptococcus pyogenes, Group A Streptococcus, Group B Streptococcus (Streptococcus agalactiae), Streptococcus pneumoniae, and Clostridium tetani.
- the infectious agent can be a bacterial pathogen that may infect host cells including, for example, Helicobacter pyloris, Legionella pneumophiHa. a bacterial strain of Mycobacteria sps. (e.g. M. tuberculosis, M. avium, M. intr acellular e, M. kansaii, or M. gordonea). Neisseria meningitides, Listeria monocytogenes, R. rickettsia, Salmonella spp., Brucella spp., Shigella spp., or certain E. coli strains or other bacteria that have acquired genes with invasive factors.
- the infectious agent can be a bacterial pathogen that is antibiotic resistant.
- the infectious agent can be a viral pathogen including, for example, coronavirus (e.g., SARS-CoV-2), Ebola, Zika, RSV, Retroviridae (e.g. human immunodeficiency viruses such as HIV-1 and HIV-LP), Picornaviridae (e.g.
- poliovirus hepatitis A virus, enterovirus, human coxsackievirus, rhinovirus, and echovirus
- rubella virus coronavirus
- vesicular stomatitis virus rabies virus
- ebola virus parainfluenza virus
- mumps virus measles virus
- respiratory syncytial virus influenza virus
- hepatitis B virus parvovirus
- Adenoviridae Herpesviridae [e.g. type 1 and type 2 herpes simplex virus (HSV), varicella-zoster virus, cytomegalovirus (CMV), and herpes virus]
- Herpesviridae e.g. type 1 and type 2 herpes simplex virus (HSV), varicella-zoster virus, cytomegalovirus (CMV), and herpes virus
- Herpesviridae e.g. type 1 and type 2 herpes simplex virus (HSV), varicella-zoster virus
- the immune binding proteins described herein can be used to boost the immunity of a subject against an infectious disease (e.g., SARS-CoV-2).
- an infectious disease e.g., SARS-CoV-2
- the immune response timing or extent may be insufficient to fight off the infection, resulting in severe complications and possibly death.
- the immune binding proteins described herein e.g., anti-SARS-CoV-2 antinbodies
- the immune binding proteins described herein are used to treat infected patients and/or passively immunize vulnerable populations facing an outbreak.
- the immune binding proteins described herein can be administered prophylactically to protect subjects from infection (e.g., by SARS-CoV-2). Such prophylactic administration of the immune binding proteins can protect at risk groups of subjects from a disease.
- the infectious agent can be a coronavirus (e.g., SARS-CoV-2), a herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), varicella zoster, Epstein-Barr, cytomegalovirus (CMV), or Kaposi’s sarcoma viruses.
- coronavirus e.g., SARS-CoV-2
- HSV-1 herpes simplex virus 1
- HSV-2 herpes simplex virus 2
- varicella zoster e.g., Epstein-Barr, cytomegalovirus (CMV), or Kaposi’s sarcoma viruses.
- CMV cytomegalovirus
- HSV-1 primarily causes oral herpes, ocular herpes, and herpes encephalitis, and occasionally causes genital herpes
- HSV-2 primarily causes genital herpes but can also cause oral herpes
- varicella zoster causes chickenpox and shingles
- Epstein-Barr causes mononucleosis and is associated with several cancers including Burkitt’s lymphoma
- CMV causes mononucleosis-like syndrome and congenital/neonatal morbidity and mortality.
- Some of the herpesviridae, and in particular HSV-1 have been associated with and proposed as causative agents for Alzheimer’s Disease.
- immune binding proteins of the invention can be used to treat and/or passively immunize against these herpesviridae.
- An injection or topical application of an antibody against HSV-1 or HSV-2 can be employed to reduce the incidence or severity of the effects of herpes outbreaks.
- the immune binding proteins described herein can be useful for treating subjects with autoimmune diseases or whom have cytokine storm response to pathogen infections (e.g., SARS- CoV-2).
- the autoimmune disease can be rheumatoid arthritis, lupus, celiac disease, Sjorgren’s syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, Type 1 diabetes, and the like.
- the immune binding proteins described herein bind the antigen target of the autoimmune disease or the SARS-CoV-2 without triggering the autoimmune/cytokine storm reaction.
- the immune binding protein could be an antibody without an Fc region, or could be an antibody in a format that does not interact with the effector cells that are associated with the autoimmune disease.
- the immune binding protein described herein binds to the autoimmune antigen without triggering an autoimmune reaction and this binding can prevent the subject’s immune system from reacting with the autoimmune antigen reducing the autoimmune disease (this can be a competitive inhibition reaction).
- FIG. 3 The work flow of FIG. 3 was adapted for making antibodies against coronavirus SARS- CoV-2. See, for example, USSN 16/826,189 filed March 21, 2020, which is hereby incorporated by reference in its entirety for all purposes.
- blood/serum samples are obtained from patients who have mounted an immune response to SARS-CoV-2 virus (from contracting SARS-CoV-2 by exposure to other infected patients).
- a solution of Pierce 1 micron beads bound to SARS-CoV-2 S1+S2 were added to the substrate, 3um BangsLabs COMPEL blue fluorescent beads loaded with a predetermined SARS-CoV-2 antigen (in some assays SARS-CoV-2 SI protein, in others SARS-CoV-2 E+M+S1+S2 protein), 3 um BangsLabs COMPEL green magnetic beads loaded with a separate predetermined SARS-CoV-2 antigen (in some assays SARS-CoV-2 RBD, in others SARS-CoV-2 S2 protein), 6um COMPEL blue magnetic beads loaded with a separate predetermined SARS-CoV-2 protein (in some assays SARS-CoV-2 Receptor Binding Domain).
- the blood/serum was depleted of T-cells and these T-cell depleted PBMC’s were loaded onto a substrate.
- PBMC’s from blood were cultured to differentiate them into plasma cells before loading onto substrate.
- the cells and beads and secondary antibody were incubated for 24 hours under appropriate culture conditions, with a goat anti-human Fab antibody bound to R- phycoerythrin (“secondary antibody”).
- secondary antibody a goat anti-human Fab antibody bound to R- phycoerythrin
- the microscope was used to identify halos of fluorescent beads that captured secreted antibodies from proximal cells due to antibody/antigen interactions and were stained with the secondary antibody.
- Reads were separated by their plate/well/chain and put through an analysis pipeline that involved clustering reads based on sequence entropy to make a consensus assembly, consensus sequences found by aligning all reads in a well/chain/plate barcode group to each assembly and making basecalls by consensus, and then annotating each sequence by alignment with IgBlast against a human germline reference database. Paired antibody genes were then synthesized, cloned into an expression vector and expressed in HEK293 cells and/or as ScFv fragments. Full length antibodies were assayed for binding with ForteBio and Luminex assays.
- Affinity of selected anti-SARS-CoV-2 antibodies was measured using mean fluorescence intensity.
- SARS-CoV-2 antigens were conjugated to Luminex beads and binding assays were performed on a Luminex200 instrument based on the manufacturer's protocol. The following antigens were tested for binding affinity: SI (Sino Biological), S2 (Sino Biological), SI + S2 (Sino Biological), RBD (Sino Biological), NAC SI (The Native Antigen Company), NAC Mosaic (The Native Antigen Company).
- Antibodies were attached to a ForteBio AHC antibody probe according to manufacturer’s recommended protocol, equilibrated and then measured against antigens. Signals from a reference sensor were subtracted from the binding measurement and a curve for a 2: 1 kinetic model was fit to the data.
- the anti-SARS-CoV-2 antibodies 219, 220 and 226 each bound to the SARS-CoV-2 RBP (receptor binding domain) with affinities of less than 1 picomolar.
- Antibodies discovered in the sequence listing are used to bind their respective proteins at their respective epitopes. Once these antibodies have bound their particular epitopes, a thiol and/or amine reactive PEGylation reagent at ImM is introduced to chemically react with amino acid side chains that are not masked by the antibody binding its epitope. The mixture is added to a Tris and/or DTT buffer to quench the PEGylation reagent and buffer exchanged. The antibody-antigen interaction is broken with heat and/or changes in pH and filtered over a Protein A/G column to remove the blocking antibodies. The resulting protein is PEGylated at all regions except the antibody binding epitope. The protein is used for vaccination in order to elicit an immune response to the original binding epitope and/or diagnostic purposes which seek to identify antibodies that bind the same epitope as the original masking antibody.
- Example 4 Development of an antibody-adjuvant vaccine
- Antibodies discovered in the sequence listing can be used to bind their respective proteins at their respective epitopes.
- the antibody/antigen mixture is used as a vaccine to elicit antibody responses at the sites unbound by the antibodies and/or improve TCR responses to the bound antigen through macrophage/dendritic cell engulfment of the antibody-antigen complex and crosspresentation of antigen peptides.
- Anti-SARS-CoV-2 antibodies were tested for neutralization activity in an in vitro assay. See, E.g., Crawford et al, Protocol and reagents for pseudotyping lentiviral particles with SARS- CoV2 Spike protein for neutralization assays, 2020, Viruses doi: 19.3390/vl2050513, which is hereby incorporated by reference in its entirety for all purposes.
- Lentivirus was engineered to express the SARS-CoV-2 spike (1+2) protein, and antibodies were tested for inhibition of infection in HEK293 cells. In this assay the pseudo typed lentivirus infect the HEK293 cells using the spike protein binding to ACE2 on the HEK293 cells.
- SC2 antibodies 3705, 3417, 3387, and 3396 all showed neutralization of SARS-CoV-2 in this in vitro assay.
- the SC2 antibody 3705 showed 100% neutralization of infection
- SC2 antibody 3417 showed about 70% neutralization
- SC2 antibody 3396 showed about 50% neutralization
- SC2 antibody 3387 showed about 45% neutralization.
- FIG. 2 A bar graph of virus neutralization by SC2 antibodies 3705, 3417 and 3387 is shown in FIG. 2.
- a line graph showing virus neutralization by SC2 antibodies 3705, 3417, and 3396 is shown in FIG. 3.
- Spike protein with mutations D614G and E484K (Sweden-1 variant of European variant B- 1), or D614G,V445I,H655Y,and E583D (England/Bristol variant of European variant B-l), or G485S (related to Australia-1 variant), or N501Y (South African variant Bl.1), or S494P, or V483K, or R683A, R685A, F817P, A892P, A899P, A942P, K986P, V987P were tested.
- Spike protein from Wuhan strains and Omicron strains was also tested.
- SC2 antibody 3387 was able to bind each of these mutants spike proteins with affinity similar to that of the wild-type spike protein.
- SC2 antibody 3387 bound to Omicron with a Kd of 409 pM, and Wuhan with a Kd of 784 pM.
- Example 7 Binding of Alpha. Beta, Gamma. Kappa, and Delta Variants by Anti-SARS-CoV-2 Antibodies
- Antigens from the following variants were tested: B.1.1.17 (Alpha) SI, B.1.1.28 (Gamma) S1+S2, 20H/501Y.V2 (Beta) SI, B.1.617 (Kappa) RBD, B.1.617.2 (Delta) RBD, Omicron RBD, Wuhan RBD, S1+S2 S494P, S1+S2 V483A, S1+S2
- SC2 antibody 3387 was able to bind each of these mutants antigens with affinity similar to that for wild-type antigen. EC50 (half maximal binding) was measured for binding of these variants by SC2 antibody 3387: beta (150 ng/ml); alpha (86 ng/ml); gamma (140 ng/ml); kappa (56 ng/ml); delta (46 ng/ml); omicron (35 ng/ml); and Wuhan (60 ng/ml).
- LentiX ACE2.S4 An ACE2 expressing HEK293T cell line (“LentiX ACE2.S4”) was constructed by packaging pCMV-AC-GFP (Origene) into lentivirus and transducing HEK293T’s. LentiX ACE2.S4 cells were grown to 85% confluency, and seeded in 96-well plates at 15k cells/well. Anti- SARS-CoV-2 antibody (SC2 antibody 3387) or a nonspecific antibody was added to wells prior to inoculation with SARS-CoV-2 Delta Variant pseudovirus (eEnzyme). The results of this are shown in FIG. 4. SC2 antibody 3387 neutralized the delta variant and greatly reduced infection of cells.
- Example 9 Neutralization of SARS-CoV-2
- Calu-3 cells were grown to confluency, and anti-SARS-CoV-2 antibody was added to the media. 40pL SARS-CoV-2 virus at a target MOI of 0.05 was added to the Calu-3 cells. After 24 hours, the supernatant was removed for TCID50 assays. Vero E6 cells were seeded at 10k cells in lOOpL per well. Infected cell culture supernatant was diluted with 950 pL D10 media, and then serial diluted. After 72 hours, wells with complete cytopathic effect were counted.
Abstract
The disclosure relates generally to the field of immune binding proteins and method for obtaining immune binding proteins from genomic or other sources. The disclosure also relates to anti-SARS-CoV-2 antibodies that have been obtained from subjects who became immune to this coronavirus, and to methods of using these anti-SARS-CoV-2 antibodies. Methods for neutralizing SARS-CoV-2 are disclosed, as well treatments for SARS-COV-2 using the anti-SARS-CoV-2 antibodies.
Description
ANTIBODIES FOR SARS-COV-2 AND USES THEREOF
REFERENCE TO SEQUENCE LISTING, TABLE OR COMPUTER PROGRAM
[1] The official copy of the Sequence Listing is submitted concurrently with the specification as an xml file, made with WIPO Sequence Version 2.1.0, via EFS-Web, with a file name of “\ABW0026.xml”, a creation date of October 6, 2022, and a size of 921 kilobytes. The Sequence Listing filed via EFS-Web is part of the specification and is incorporated in its entirety by reference herein.
BACKGROUND OF THE DISCLOSURE
[2] There is considerable interest in being able to discover antibodies to specific antigens. Such antibodies are useful as research tools and for diagnostic and therapeutic applications. However, the identification of such useful antibodies is difficult and once identified, these antibodies often require considerable redesign before they are suitable for therapeutic applications in humans.
[3] Many methods for identifying antibodies involve display of antibody libraries derived by amplification of nucleic acids from B cells or other tissues. These approaches have limitations that limit the useful antibodies obtained from the library. For example, most antibody libraries do not pair the heavy and light chains obtained from memory B-cells or plasma cells that have mounted an effective immune response against an immunological challenge. In addition, most human antibody libraries known contain only the antibody sequence diversity that can be experimentally captured or cloned from a biological source (e.g., B cells). Accordingly, such libraries may overrepresent some sequences, while completely lacking or under-representing other sequences especially paired light and heavy chains that form useful antibodies, particularly those from a successful immune response.
[4] It is an object of this invention to provide libraries of immune binding proteins that are enriched for useful immune binding proteins. It is also an obj ect of the invention to provide methods for making such libraries that are enriched for useful multimers of immune binding proteins. It is a further object of the invention to provide methods for amplifying nucleic acids from B-cells and plasma cells so that the pairing of light and heavy chains is maintained. It is an object of the invention to obtain libraries of antibodies relevant to disease therapies by obtaining paired light and heavy chain antibodies from individuals whom have mounted antibody responses against a variety of immunologic challenges related to, for example, infectious diseases (an infectious agent), cancer, auto-immune disease, neurodegenerative disease, and allergies.
[5] SARS-CoV-2 is the causative agent, the virus that causes, COVID-19. It is novel coronavirus that first infected humans starting in December 2019. At the time of the filing of this application SARS-CoV-2 had infected at least 1,279,546 person in the United States, and had killed
at least 76,527 persons. There is a present unmet medical need for therapies to treat SARS-CoV-2 infections and reduce the morbidity and mortality of this disease in the United States and around the world.
SUMMARY OF THE INVENTION
[6] The disclosure relates to antibodies obtained from subjects who acquired immunity to coronavirus, SARS-CoV-2. Over a thousand human antibodies have been obtained from these subjects in a screening to identify antibody clones that bound to targets from SARS-CoV-2. The targets or mixture of targets used to identify the anti-SARS-CoV-2 antibodies were SARS-CoV-2 Spike 1 Protein (SI), SARS-CoV-2 Spike 2 Protein (S2), SARS-CoV-2 Receptor Binding Domain, SARS-CoV-2 Spike 1 Protein OR SARS-CoV-2 Spike 2 Protein (S1+S2), SARS-CoV-2 Spike 1 Protein OR SARS-CoV-2 S2 Protein OR SARS-CoV-2 Membrane Protein OR SARS-CoV-2 Envelope Protein (S1+S2+E+M). The nucleic acid and amino acid sequences of the variable region heavy chains and light chains for these anti-SARS-CoV-2 antibodies are disclosed herein. The antibodies can be monoclonal, and can be fully human antibodies, chimeric antibodies, or CDR- grafted antibodies. The antibodies can be full length or and antibody fragment. Antibody fragments include any of the well-known formats or types, including for example, antigen-binding fragments (Fab), single chain variable fragments (scFv) and “third generation” (3G).
[7] Specific antibodies disclosed herein include, for example, anti-SARS-CoV-2 (SC2) antibody 3417 (SC2 Ab 3417 or 3417), SC2 antibody 3387 (3387), SC2 antibody 3705 (3705), SC2 antibody 3388 (3388), SC2 antibody 3396 (3396), SC2 antibody 3908 (3908), SC2 antibody 3916 (3916), SC2 antibody 3929 (3929), SC2 antibody 3940 (3940), SC2 antibody 4021 (4021). Several antibodies, including SC2 antibody 3387 (3387) and SC2 antibody 3705 (3705) have shown affinity for various variants of SARS-CoV-2 now present in the population. Several antibodies including SC2 antibody 3387 (3387), SC2 antibody 3705 (3705), SC antibody 3396, and SC2 antibody 3417 (3417) have also shown neutralizing activity against SARS-CoV-2.
[8] The anti-SARS-CoV-2 antibodies can be full length antibodies such as, for example, an IgG (e.g., IgGl, IgG2, IgG3, or IgG4), an IgM, an IgA, an IgD, or an IgE. The anti-SARS-CoV-2 antibody can be an antibody fragment such as, for example, a Fab, F(ab’)2, single chain antibody (scFv), Fv, or other antibody fragments made from recombinant nucleic acids encoding fragments of the antibody chains. The antibody fragments can also be made by digestion of an anti-SARS- CoV-2 antibody to generate a smaller fragment. The anti-SARS-CoV-2 antibody can be obtained from a B-cell, a plasma cell, a B memory cell, a pre-B-cell or a progenitor B-cell.
[9] Compositions and formulations described here can comprise one or more of the anti-SARS- CoV-2 antibodies for administration to a subject. The compositions with the anti-SARS-CoV-2
antibodies can also include other drugs or agents for treatment of the subject. For example, the anti-SARS-CoV-2 antibody compositions can include analgesics, other antiviral drugs, other antiviral antibodies, and/or agents that reduce symptoms caused by infection with SARS-CoV-2.
[10] Methods described herein use the anti-SARS-CoV-2 antibodies to neutralize (e.g., in vitro or in vivo or both) the SARS-CoV-2 virus and inhibit the virus from infecting cells. The methods can be used to treat subjects with active infections from SARS-CoV-2 and thereby reduce the symptoms in a subject, time of infection of the subject, or transmission of virus to others by the infected subject. The methods can also be used prophylactically to reduce, inhibit, or prevent infection of a subject by the SARS-CoV-2 virus.
BRIEF DESCRIPTION OF THE FIGURES
[11] FIG. 1 (3) shows a work flow chart for obtaining clones expressing a desired antigen binding protein using a single cell selecting device.
[12] FIG. 2 shows a bar graph of virus neutralization by the anti-SARS-CoV2 antibodies.
[13] FIG. 3 shows a line graph of virus neutralization by the anti-SARS-CoV2 antibodies.
[14] FIG. 4 shows a line graph of neutralization of the delta variant by SARS-CoV-2 antibody (SC2 antibody 3387).
[15] FIG. 5 shows a line graph of neutralization activity of Wuhan-1 by anti-SARS-CoV-2 antibodies.
[16] FIG. 5 shows bar graphs of viral titer in Hamsters inoculated with SARS-CoV-2 after prophylactic treatment with an anti-SARS-CoV-2 antibody.
DETAILED DESCRIPTION OF THE INVENTION
[17] Before the various embodiments are described, it is to be understood that the teachings of this disclosure are not limited to the particular embodiments described, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present teachings will be limited only by the appended claims.
[18] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present teachings, some exemplary methods and materials are now described.
[19] It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims can be drafted to exclude any optional element. As such, this statement is
intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements or use of a “negative” limitation. Numerical limitations given with respect to concentrations or levels of a substance are intended to be approximate, unless the context clearly dictates otherwise. Thus, where a concentration is indicated to be (for example) 10 micrograms (“pg”), it is intended that the concentration be understood to be at least approximately or about 10 pg.
[20] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which can be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present teachings. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.
Definitions
[21] As used herein, an “antibody” refers to a protein functionally defined as a binding protein and structurally defined as comprising an amino acid sequence that is recognized as being derived from the framework region of an immunoglobulin encoding gene of an animal producing antibodies. An antibody can consist of one or more polypeptides substantially encoded by immunoglobulin genes or fragments of immunoglobulin genes. The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
[22] A typical immunoglobulin (antibody) structural unit is known to comprise a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chains respectively.
[23] Antibodies exist as intact immunoglobulins or as a number of well-characterized fragments. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'2, a dimer of Fab which itself is a light chain joined to VH-CH1 by a disulfide bond. The F(ab)'2 may be reduced under mild conditions to break the disulfide linkage in the hinge region thereby converting the (Fab')2 dimer into an Fab' monomer. The Fab' monomer is essentially an Fab with part of the hinge region (see, Fundamental Immunology, W. E. Paul, ed., Raven Press, N.Y.
(1993), for a more detailed description of other antibody fragments). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that fragments can be synthesized de novo either chemically or by utilizing recombinant DNA methodology. Thus, the term antibody, as used herein also includes antibody fragments either produced by the modification of whole antibodies or synthesized using recombinant DNA methodologies. Preferred antibodies include VH-VL dimers, including single chain antibodies (antibodies that exist as a single polypeptide chain), such as single chain Fv antibodies (sFv or scFv) in which a variable heavy and a variable light region are joined together (directly or through a peptide linker) to form a continuous polypeptide. The single chain Fv antibody is a covalently linked VH-VL heterodimer which may be expressed from a nucleic acid including VH- and VL- encoding sequences either joined directly or joined by a peptide-encoding linker (e.g., Huston, et al. Proc. Nat. Acad. Sci. USA, 85:5879-5883, 1988). While the VH and VL are connected to each as a single polypeptide chain, the VH and VL domains associate non-covalently. Alternatively, the antibody can be another fragment. Other fragments can also be generated, including using recombinant techniques. For example, Fab molecules can be displayed on phage if one of the chains (heavy or light) is fused to g3 capsid protein and the complementary chain exported to the periplasm as a soluble molecule. The two chains can be encoded on the same or on different replicons; the two antibody chains in each Fab molecule assemble post-translationally and the dimer is incorporated into the phage particle via linkage of one of the chains to g3p (see, e.g., U.S. Pat. No: 5,733,743). The scFv antibodies and a number of other structures converting the naturally aggregated, but chemically separated light and heavy polypeptide chains from an antibody V region into a molecule that folds into a three-dimensional structure substantially similar to the structure of an antigen-binding site are known to those of skill in the art (see e.g., U.S. Pat. Nos. 5,091,513, 5,132,405, and 4,956,778). In some embodiments, the scFv is a diabody as described in Holliger et al., Proc. Nat’ 1 Acad. Sci. vol. 90, pp. 6444-6448 (1993), which is incorporated by reference in its entirety for all purposes. In some embodiments, antibodies include all those that have been displayed on phage or generated by recombinant technology using vectors where the chains are secreted as soluble proteins, e.g., scFv, Fv, Fab, pr (Fab')2 or generated by recombinant technology using vectors where the chains are secreted as soluble proteins. Antibodies can also include diantibodies and miniantibodies.
[24] Antibodies of the invention also include heavy chain dimers, such as antibodies from camelids. Since the VH region of a heavy chain dimer IgG in a camelid does not have to make hydrophobic interactions with a light chain, the region in the heavy chain that normally contacts a
light chain is changed to hydrophilic amino acid residues in a camelid. VH domains of heavy-chain dimer IgGs are called VHH domains.
[25] In camelids, the diversity of antibody repertoire is determined by the complementary determining regions (CDR) 1, 2, and 3 in the VH or VHH regions. The CDR3 in the camel VHH region is characterized by its relatively long length averaging 16 amino acids (Muyldermans et al., 1994, Protein Engineering 7(9): 1129). This is in contrast to CDR3 regions of antibodies of many other species. For example, the CDR3 of mouse VH has an average of 9 amino acids.
[26] Libraries of camelid-derived antibody variable regions, which maintain the in vivo diversity of the variable regions of a camelid, can be made by, for example, the methods disclosed in U.S. Patent Application Ser. No. 20050037421, published Feb. 17, 2005.
[27] As used herein, “HA,” “NB,” and “NA” respectively mean hemagglutinin, NB protein and neuraminidase. HA, NB and NA are antigenic glycoproteins located on the surface of influenza viruses. These glycoproteins are responsible for the binding the virus to the cell that is to be infected and processes that result in infection with the virus.
[28] As used herein, the term “naturally occurring” means that the components are encoded by a single gene that was not altered by recombinant means and that pre-exists in an organism, e.g., in an antibody library that was created from naive cells or cells that were exposed to an antigen.
[29] As used herein, the term “antigen” refers to substances that are capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, such as, with specific antibodies or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulates, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (epitopes) combines with the antibody or a specific receptor on a lymphocyte. More broadly, the term "antigen" may be used to refer to any substance to which an antibody binds, or for which antibodies are desired, regardless of whether the substance is immunogenic. For such antigens, antibodies may be identified by recombinant methods, independently of any immune response.
[30] As used herein, the term “epitope” refers to the site on an antigen or hapten to which specific B cells and/or T cells respond. The term is also used interchangeably with "antigenic determinant" or "antigenic determinant site". Epitopes include that portion of an antigen or other macromolecule capable of forming a binding interaction that interacts with the variable region binding pocket of an antibody.
[31] As used herein, the term “binding specificity” of an antibody refers to the identity of the antigen to which the antibody binds, preferably to the identity of the epitope to which the antibody binds.
[32] As used herein, the term “chimeric polynucleotide” means that the polynucleotide comprises regions which are wild-type and regions which are mutated. It may also mean that the polynucleotide comprises wild-type regions from one polynucleotide and wild-type regions from another related polynucleotide.
[33] As used herein, the term “chimeric polynucleotide” means that the polynucleotide comprises regions which are wild-type and regions which are mutated. It may also mean that the polynucleotide comprises wild-type regions from one polynucleotide and wild-type regions from another related polynucleotide.
[34] As used herein, the term “complementarity-determining region” or “CDR” refer to the art- recognized term as exemplified by the Kabat and Chothia. CDRs are also generally known as hypervariable regions or hypervariable loops (Chothia and Lesk (1987) J Mol. Biol. 196: 901; Chothia et al. (1989) Nature 342: 877; E. A. Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md.) (1987); and Tramontane et al. (1990) J Mol. Biol. 215: 175). “Framework region” or “FR” refers to the region of the V domain that flank the CDRs. The positions of the CDRs and framework regions can be determined using various well known definitions in the art, e.g., Kabat, Chothia, international ImMunoGeneTics database (IMGT), and AbM (see, e.g., Johnson et al., supra; Chothia & Lesk, 1987, Canonical structures for the hypervariable regions of immunoglobulins. J. Mol. Biol. 196, 901-917; Chothia C. et al., 1989, Conformations of immunoglobulin hypervariable regions. Nature 342, 877-883; Chothia C. et al., 1992, structural repertoire of the human VH segments J. Mol. Biol. 227, 799-817; Al-Lazikani et al., J. Mol. Biol 1997, 273(4)). Definitions of antigen combining sites are also described in the following: Ruiz et al., IMGT, the international ImMunoGeneTics database. Nucleic Acids Res., 28, 219-221 (2000); and Lefranc, M.-P. IMGT, the international ImMunoGeneTics database. Nucleic Acids Res. Jan l;29(l):207-9 (2001); MacCallum et al, Antibody-antigen interactions: Contact analysis and binding site topography, J. Mol. Biol., 262 (5), 732-745 (1996); and Martin et al, Proc. Natl Acad. Sci. USA, 86, 9268-9272 (1989); Martin, et al, Methods Enzymol., 203, 121-153, (1991); Pedersen et al, Immunomethods, 1, 126, (1992); and Rees et al, In Sternberg M. J. E. (ed.), Protein Structure Prediction. Oxford University Press, Oxford, 141-172 1996).
[35] The term “conservative substitution” refers to substitution of an amino acid in a polypeptide with a functionally, structurally or chemically similar natural or unnatural amino acid. In certain
embodiments, the following groups each contain natural amino acids that are conservative substitutions for one another:
1) Glycine (Gly/G), Alanine (Ala/ A);
2) Isoleucine (Ile/I), Leucine (Leu/L), Methionine (Met/M), Valine (Val/V);
3) Phenylalanine (Phe/F), Tyrosine (Tyr/Y), Tryptophan (Trp/W);
4) Serine (Ser/S), Threonine (Thr/T), Cysteine (Cys/C);
5) Asparagine (Asn/N), Glutamine (Gln/Q);
6) Aspartic acid (Asp/D), Glutamic acid (Glu/E); and
7) Arginine (Arg/R), Lysine (Lys/K), Histidine (His/H).
[36] As used herein, the term “hapten” is a small molecule that, when attached to a larger carrier such as a protein, can elicit an immune response in an organism, e.g., such as the production of antibodies that bind specifically to it (in either the free or combined state). A “hapten” is able to bind to a preformed antibody, but may fail to stimulate antibody generation on its own. In the context of this invention, the term “hapten” includes modified amino acids, either naturally occurring or non-naturally occurring. Thus, for example, the term “hapten” includes naturally occurring modified amino acids such as phosphotyrosine, phosphothreonine, phosphoserine, or sulphated residues such as sulphated tyrosine (sulphotyrosine), sulphated serine (sulphoserine), or sulphated threonine (sulphothreonine); and also include non-naturally occurring modified amino acids such as p-nitro-phenylalanine.
[37] As used herein, the term “heterologous” when used with reference to portions of a polynucleotide indicates that the nucleic acid comprises two or more subsequences that are not normally found in the same relationship to each other in nature. For instance, the nucleic acid is typically recombinantly produced, having two or more sequences, e.g., from unrelated genes arranged to make a new functional nucleic acid. Similarly, a “heterologous” polypeptide or protein refers to two or more subsequences that are not found in the same relationship to each other in nature.
[38] As used herein, the term “host cell” refers to a prokaryotic or eukaryotic cell into which the vectors of the invention may be introduced, expressed and/or propagated. A microbial host cell is a cell of a prokaryotic or eukaryotic micro-organism, including bacteria, yeasts, microscopic fungi and microscopic phases in the life-cycle of fungi and slime molds. Typical prokaryotic host cells include various strains of E. coli. Typical eukaryotic host cells are yeast or filamentous fungi, or
mammalian cells, such as Chinese hamster ovary cells, murine NIH 3T3 fibroblasts, human embryonic kidney 193 cells, or rodent myeloma or hybridoma cells.
[39] As used herein, the term “immunological response” to a composition or vaccine is the development in the host of a cellular and/or antibody-mediated immune response to a composition or vaccine of interest. Usually, an “immunological response” includes but is not limited to one or more of the following effects: the production of antibodies, B cells, helper T cells, and/or cytotoxic T cells, directed specifically to an antigen or antigens included in the composition or vaccine of interest. Preferably, the host will display either a therapeutic or protective immunological response such that resistance to new infection will be enhanced and/or the clinical severity of the disease reduced. Such protection will be demonstrated by either a reduction or lack of symptoms normally displayed by an infected host, a quicker recovery time and/or a lowered viral titer in the infected host.
[40] As used herein, the term “isolated” refers to a nucleic acid or polypeptide separated not only from other nucleic acids or polypeptides that are present in the natural source of the nucleic acid or polypeptide, but also from polypeptides, and preferably refers to a nucleic acid or polypeptide found in the presence of (if anything) only a solvent, buffer, ion, or other component normally present in a solution of the same. The terms “isolated” and “purified” do not encompass nucleic acids or polypeptides present in their natural source.
[41] As used herein, the term “mammal” refers to warm-blooded vertebrate animals all of which possess hair and suckle their young.
[42] As used herein, “percentage of sequence identity” and “percentage homology” are used interchangeably herein to refer to comparisons among polynucleotides or polypeptides, and are determined by comparing two optimally aligned sequences over a comparison window, where the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence for optimal alignment of the two sequences. The percentage may be calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity. Alternatively, the percentage may be calculated by determining the number of positions at which either the identical nucleic acid base or amino acid residue occurs in both sequences or a nucleic acid base or amino acid residue is aligned with a gap to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence
identity. Those of skill in the art appreciate that there are many established algorithms available to align two sequences. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman, Adv Appl Math. 2:482, 1981; by the homology alignment algorithm of Needleman and Wunsch, J Mol Biol. 48:443, 1970; by the search for similarity method of Pearson and Lipman, Proc Natl Acad Sci. USA 85:2444, 1988; by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the GCG Wisconsin Software Package), or by visual inspection (see generally, Current Protocols in Molecular Biology, F. M. Ausubel et al., eds., Greene Publishing Associates, Inc. and John Wiley & Sons, Inc., (1995 Supplement). Examples of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., J. Mol. Biol. 215:403-410, 1990; and Altschul et al., Nucleic Acids Res. 25(17):3389-3402, 1977; respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information website. BLAST for nucleotide sequences can use the BLASTN program with default parameters, e.g., a wordlength (W) of 11, an expectation (E) of 10, M=5, N=-4, and a comparison of both strands. BLAST for amino acid sequences can use the BLASTP program with default parameters, e.g., a wordlength (W) of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff, Proc Natl Acad Sci. USA 89: 10915, 1989). Exemplary determination of sequence alignment and % sequence identity can also employ the BESTFIT or GAP programs in the GCG Wisconsin Software package (Accelrys, Madison WI), using default parameters provided.
[43] The term “pharmaceutically acceptable” refers to a substance (e.g., an active ingredient or an excipient) that is suitable for use in contact with the tissues and organs of a subject without excessive irritation, allergic response, immunogenicity and toxicity, is commensurate with a reasonable benefit/risk ratio, and is effective for its intended use. A “pharmaceutically acceptable” excipient or carrier of a pharmaceutical composition is also compatible with the other ingredients of the composition.
[44] As used herein, the terms “protein”, “peptide”, “polypeptide” and “polypeptide fragment” are used interchangeably herein to refer to polymers of amino acid residues of any length. The polymer can be linear or branched, it may comprise modified amino acids or amino acid analogs, and it may be interrupted by chemical moieties other than amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling or bioactive component.
[45] As used herein, the term “protracting moiety” means a molecule that can be attached to a polypeptide (e.g., an antibody light and/or heavy chain) to increase its molecular weight so that the polypeptide’s residence time in the blood (and/or serum) is increased. For example, the protracting moiety can increase the serum/blood half-life of the polypeptide. The increased half-life or residence time can be the result of, for example, reduced glomerular filtration by the kidney, and/or reduced uptake by the liver, and/or reduced binding and removal by immune binding proteins, etc. A protracting moiety can be, for example, another polypeptide, a polymer (e.g., synthetic polymer, natural polymer, etc.), etc.
[46] As used herein, the term “purified” means that the indicated nucleic acid or polypeptide is present in the substantial absence of other biological macromolecules, e.g., polynucleotides, proteins, and the like. In one embodiment, the polynucleotide or polypeptide is purified such that it constitutes at least 95% by weight, more preferably at least 99.8% by weight, of the indicated biological macromolecules present (but water, buffers, and other small molecules, especially molecules having a molecular weight of less than 1000 daltons, can be present).
[47] As used herein, the terms “RBD”, “SI”, “S2”, “EP”, and “MP” mean, respectively, SARS- CoV-2 receptor binding domain (RBD), SARS-CoV-2 Spike 1 protein (SI), SARS-CoV-2 Spike 2 protein (S2), SARS-CoV-2 Envelope Proteins (EP), and SARS-CoV-2 Membrane Protein (MP).
[48] As used herein, the term “recombinant nucleic acid” refers to a nucleic acid in a form not normally found in nature. That is, a recombinant nucleic acid is flanked by a nucleotide sequence not naturally flanking the nucleic acid or has a sequence not normally found in nature. Recombinant nucleic acids can be originally formed in vitro by the manipulation of nucleic acid by restriction endonucleases, or alternatively using such techniques as polymerase chain reaction. It is understood that once a recombinant nucleic acid is made and reintroduced into a host cell or organism, it will replicate non-recombinantly, i.e., using the in vivo cellular machinery of the host cell rather than in vitro manipulations; however, such nucleic acids, once produced recombinantly, although subsequently replicated non-recombinantly, are still considered recombinant for the purposes of the invention.
[49] As used herein, the term “recombinant polypeptide” refers to a polypeptide expressed from a recombinant nucleic acid, or a polypeptide that is chemically synthesized in vitro.
[50] As used herein, the term “recombinant variant” refers to any polypeptide differing from naturally occurring polypeptides by amino acid insertions, deletions, and substitutions, created using recombinant DNA techniques. Guidance in determining which amino acid residues may be replaced, added, or deleted without abolishing activities of interest, such as enzymatic or binding activities, may be found by comparing the sequence of the particular polypeptide with that of
homologous peptides and minimizing the number of amino acid sequence changes made in regions of high homology.
[51] Preferably, amino acid “substitutions” are the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, i.e., conservative amino acid replacements. Amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved. For example, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine; polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine; positively charged (basic) amino acids include arginine, lysine, and histidine; and negatively charged (acidic) amino acids include aspartic acid and glutamic acid.
[52] As used herein, the term “SARS-CoV-2” means the Severe acute respiratory syndrome coronavirus 2 that cause the illness COVID-19. SARS-CoV-2 includes the strains and sub-strains of coronavirus that are arising during this outbreak of SARS-CoV-2.
[53] The term “stringent hybridization conditions” refers to hybridizing in 50% formamide at 5XSSC at a temperature of 42 °C and washing the filters in 0.2XSSC at 60 °C. (1XSSC is 0.15M NaCl, 0.015M sodium citrate.) Stringent hybridization conditions also encompasses low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50 °C; hybridization with a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42 °C; or 50% formamide, 5XSSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5XDenhardt' s solution, sonicated salmon sperm DNA (50 pg/ml), 0.1% SDS, and 10% dextran sulfate at 42 °C, with washes at 42 °C in 0.2XSSC (sodium chloride/sodium citrate) and 50% formamide at 55 °C, followed by a high- stringency wash consisting of 0.1XSSC containing EDTA at 55 °C.
[54] The term “substantially homologous” or “substantially identical” in the context of two polypeptides or polynucleotides refers to two or more sequences or subsequences that have at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid or nucleic acid residue identity, when compared and aligned for maximum correspondence, as measured using a sequence comparison algorithm or by visual inspection. The terms “substantially homologous” or “substantially identical” can mean at least about 70% amino acid or nucleic acid residue identity. The term “substantially homologous” or “substantially identical” can mean at least about 85% amino acid or nucleic acid residue identity. The substantial homology or identity can
exist over a region of the sequences that is at least about 20, 30, 40, 50, 100, 150 or 200 residues in length. The sequences can be substantially homologous or identical over the entire length of either or both comparison biopolymers.
[55] Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman, Adv. Appl. Math., 2:482 (1981); by the homology alignment algorithm of Needleman and Wunsch, J. Mol. Biol., 48:443 (1970); by the search for similarity method of Pearson and Lipman, Proc. Natl. Acad. Sci. USA, 85:2444 (1988); by computerized implementations of these algorithms (e.g., GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, Madison, Wisconsin); or by visual inspection.
[56] One example of a useful algorithm is PILEUP. PILEUP creates a multiple sequence alignment from a group of related sequences using progressive, pairwise alignments to show relationship and percent sequence identity. It also plots a tree or dendogram showing the clustering relationships used to create the alignment. PILEUP uses a simplification of the progressive alignment method of Feng and Doolittle, J. Mol. Evol., 35:351-360 (1987). The method used is similar to the method described by Higgins and Sharp, CABIOS, 5: 151-153 (1989). The program can align up to about 300 sequences, each having a maximum length of about 5,000 nucleotides or amino acids. The multiple alignment procedure begins with the pairwise alignment of the two most similar sequences, producing a cluster of two aligned sequences. This cluster is then aligned to the next most related sequence or cluster of aligned sequences. Two clusters of sequences are aligned by a simple extension of the pairwise alignment of two individual sequences. The final alignment is achieved by a series of progressive, pairwise alignments. The program is run by designating specific sequences and their amino acid or nucleotide coordinates for regions of sequence comparison and by designating the program parameters. For example, a reference sequence can be compared to other test sequences to determine the percent sequence identity relationship using the following parameters: default gap weight (3.00), default gap length weight (0.10), and weighted end gaps. Another algorithm that is useful for generating multiple alignments of sequences is Clustal W (see, e.g., Thompson et al., Nucleic Acids Research, 22:4673-4680 [1994]).
[57] Another example of an algorithm that is suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm, which is described in Altschul et al., J. Mol. Biol., 215:403-410 (1990). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information. This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the
same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul 1990). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are then extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always < 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction is halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults, e.g., a wordlength (W) of 11, an expectation (E) of 10, M = 5, N = -4, and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults, e.g., a wordlength (W) of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff, Proc. Natl. Acad. Sci. LISA, 89: 10915 [1989]).
[58] In addition to calculating percent sequence identity, the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul, Proc. Natl. Acad. Sci. USA, 90:5873-5787 [1993]). One measure of similarity provided by the BLAST algorithm is the smallest sum probability [P(N)], which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. In certain embodiments, a polynucleotide is considered similar to a reference sequence if the smallest sum probability in a comparison of the test polynucleotide to the reference polynucleotide is less than about 0.1, 0.01 or 0.001.
[59] A polypeptide can be substantially homologous or identical to a second polypeptide if the two polypeptides differ only by conservative amino acid substitutions. Two nucleic acid sequences can be substantially homologous or identical if the two polynucleotides hybridize to each other under stringent conditions, or under highly stringent conditions, as described herein.
[60] The term “therapeutically effective amount” refers to an amount of a compound that, when administered to a subject, is sufficient to prevent, reduce the risk of developing, delay the onset of, slow the progression or cause regression of the medical condition being treated, or to alleviate to some extent the medical condition or one or more symptoms or complications of that condition. The term “therapeutically effective amount” also refers to an amount of a compound that is
sufficient to elicit the biological or medical response of a cell, tissue, organ, system, animal or human which is sought by a researcher, veterinarian, medical doctor or clinician.
[61] The singular terms “a”, “an”, and “the” include plural referents unless context clearly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise. Numerical limitations given with respect to concentrations or levels of a substance, such as an antigen, are intended to be approximate. Thus, where a concentration is indicated to be at least (for example) 200 pg, it is intended that the concentration be understood to be at least approximately “about” or “about” 200 pg.
Anti-SARS-CoV-2 Antibodies
[62] Antibodies are immune binding proteins that are structurally defined as comprising an amino acid sequence recognized as being derived from the framework region of an immunoglobulin. An antibody can consist of one or more polypeptides substantially encoded by immunoglobulin genes or fragments of immunoglobulin genes. The immunoglobulin genes can include, for example, the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as myriad immunoglobulin variable region genes. Antibody light chains can be classified as either kappa or lambda. Antibody heavy chains can be classified as gamma, mu, alpha, delta, or epsilon, which in turn can define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
[63] Antibodies can exist as intact immunoglobulins or as a number of well-known fragments. Pepsin digests an antibody below the disulfide linkages in the hinge region and can produce F(ab)'2, a dimer of Fab which itself is a light chain joined to VH-CH1 by a disulfide bond. The F(ab)'2 may be reduced under mild conditions to break the disulfide linkage in the hinge region thereby converting the (Fab')2 dimer into Fab' monomers. The Fab' monomer can be an Fab with part of the hinge region (see, Fundamental Immunology, W. E. Paul, ed., Raven Press, N.Y. (1993), which is incorporated by reference in its entirety for all purposes). Antibody fragments can also be synthesized de novo either chemically or by utilizing recombinant DNA methodology. Antibodies can include VH-VL dimers, including single chain antibodies (antibodies that exist as a single polypeptide chain), diabodies, or single chain Fv antibodies (sFv or scFv) in which a variable heavy and a variable light region are joined together (directly or through a peptide linker) to form a continuous polypeptide, (e.g., Huston, et al. Proc. Nat. Acad. Sci. USA, 85:5879-5883, 1988, which is incorporated by reference in its entirety for all purposes). Antibodies can also include other fragments, including, for example, Fab molecules displayed on phage if one of the chains (heavy or light) is fused to g3 capsid protein and the complementary chain exported to the periplasm as a soluble molecule, (e.g., U.S. Pat. No: 5,733,743, which is incorporated by reference in its entirety
for all purposes). The antibody can be an scFv antibody or a number of other structures converting the naturally aggregated, but chemically separated light and heavy polypeptide chains from an antibody V region into a molecule that folds into a three dimensional structure substantially similar to the structure of an antigen-binding site are known to those of skill in the art (e.g., U.S. Pat. Nos. 5,091,513, 5,132,405, and 4,956,778, which are all incorporated by reference in their entirety for all purposes). The scFv can be a diabody as described in Holliger et al., Proc. Nat’l Acad. Sci. vol. 90, pp. 6444-6448 (1993), which is incorporated by reference in its entirety for all purposes. Antibodies include all those that have been displayed on phage or generated by recombinant technology using vectors where the chains are secreted as soluble proteins, e.g., scFv, Fv, Fab, pr (Fab'X Antibodies can also include miniantibodies. The antibody can be obtained from a B-cell, a plasma cell, a B memory cell, a pre-B-cell or a progenitor B-cell.
[64] The antibodies can be monoclonal, and can be fully human antibodies, chimeric antibodies, or CDR-grafted antibodies. The antibodies can be full length or and antibody fragment. Antibody fragments include any of the well-known formats or types, including for example, antigen-binding fragments (Fab), single chain variable fragments (scFv) and “third generation” (3G). Nelson, MAbs 2010, 2:77-83, doi: 10.4161/mabs.2.1.10786, which is incorporated by reference in its entirety for all purposes. F(ab')2, Fab, Fab' and Fv are examples of antigen-binding fragments that can be generated from the variable region of IgG and IgM.
[65] Anti-SARS-CoV-2 antibody 3417 can have a variable region comprised of a heavy chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSQVQLQESGPGLLKPSQTLSLTCTVSGVSIRNSNYFWNWIR RPAGKGLEWIGRMHSGGTTNYNPSLKSRVTVSSDAARNQFSLELTSVTAADTAVYYCAR DDPLNRFAAFQIWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1)
This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of: ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT CGCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGCTGAAGCCCTCGCAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGTCTCCATCAGAAATAGTAATTACTTCTGGAATTG GATCCGGCGGCCCGCCGGGAAGGGACTGGAGTGGATTGGGCGTATGCATAGTGGTG
GGACCACCAATTACAATCCCTCCCTCAAGAGTCGGGTCACCGTGTCAAGTGACGCGG CCAGGAACCAGTTCTCCCTGGAGTTGACCTCTGTGACCGCCGCAGACACGGCCGTGT ATTACTGTGCGAGAGATGACCCCCTTAACCGGTTCGCTGCTTTTCAAATCTGGGGCCG AGGGACACTGGTCACCGTCTCTTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTG
GCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG GACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACA
AGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCT
TCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCG TGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACG
GCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACG
TACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAG TACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCC AAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGA GGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAG
CGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGA CAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCT GCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO:
2)
Anti-SARS-CoV-2 antibody 3417 can have a variable region comprised of a light chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNKYISWYQQLP GTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSSLSVFYVF GTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKA GVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ
ID NO: 3)
This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT
CGCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCA CCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAAATATATATCCTGGTACCA GCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTC
AGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATC ACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCAG CCTGAGTGTTTTTTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTGGGTCAGCCC AAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACA AGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCT GGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAA CAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTG GAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGA AGACAGTGGCCCCTACAGAATGTTCATAG (SEQ ID NO: 4)
[66] Anti-SARS-CoV-2 antibody 3387 can have a variable region comprised of a heavy chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSQVQLVQSGAEVMQVGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWINTYNGNTNYAQKLQGRVTMTTDTSTTTAYMELRSLRSDDTAVYY CARVAVGYCSGGSCYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KD YFPEP VT VSWNSGALTSGVHTFP AVLQS SGL YSLS S VVTVPS S SLGTQT YICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVI<FNWYVDGVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CI<VS NKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK (SEQ ID NO: 5)
This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of: ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT CGCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGATGCAAGTGGGGGCCTCAGTGA AGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAGCTATGGTATCAGCTGGGTGCG ACAGGCCCCCGGACAAGGGCTTGAGTGGATGGGATGGATCAACACTTACAATGGTA ACACAAACTATGCACAGAAGCTCCAGGGCAGAGTCACCATGACCACAGACACATCC ACGACCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTAT TACTGTGCGAGAGTCGCTGTAGGATATTGCAGTGGTGGTAGCTGCTACTACTTTGACT ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGG TCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCT GCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC TGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCT CAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAA CGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTT
GTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGT
CAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA
GGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTG
GTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGT
ACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGA
AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCC
CATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCT
TCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAAC
TACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGC
TCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGC
ATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAT GA (SEQ ID NO: 6).
Anti-SARS-CoV-2 antibody 3387 can have a variable region comprised of a light chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSPEIVMTQSPATLSVSPGERATLSCRASQSVSNNLAWYQQK
PGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNDWPPSWTF GQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 7)
This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT
CACCGGAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAA
GAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAACAACTTAGCCTGGTACC
AGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCA
CTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGAACAGAGTTCACTCTCACCA
TCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATGACTG
GCCTCCGTCTTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGC
TGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCC
TCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAG
GTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAG
CAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACG AGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCA CAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 8)
[67] Anti-SARS-CoV-2 antibody 3705 is a single chain antibody with the amino acid sequence of:
MKYLLPTAAAGLLLLAAQPAMALEIVMTQSPATLSVSPGERATLSCRASQSVSNNLAWY QQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNDWPPS WTFGQGTKVEIKGGGGSGGGGSGGGGSQVQLVQSGAEVMQVGASVKVSCKASGYTFT SYGISWVRQAPGQGLEWMGWINTYNGNTNYAQKLQGRVTMTTDTSTTTAYMELRSLR SDDT AVYYC ARVAVGYC SGGSC YYFDYWGQGTL VTVS SGGGGSGGQHHHHHHGAEQ
KLISEEDLGSGKPIPNPLLGLDSTS (SEQ ID NO: 9)
This amino acid sequence can be encoded in a nucleic acid sequence of:
ATGAAATACCTATTGCCTACGGCGGCCGCTGGATTGTTATTACTCGCGGCCCAGCCG
GCCATGGCATTAGAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCA GGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAACAACTTAGCC
TGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACC AGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGAACAGAGTTCACT
CTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATA ATGACTGGCCTCCGTCTTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAAGGAG GAGGAGGCTCTGGGGGCGGCGGTTCTGGAGGAGGTGGAAGTcaggtgcagctggttcagtctggcg ccgaagtgatgcaagtgggggcatcagtgaaggtgtcctgtaaggcttccggttatacctttaccagctatggaatctcgtgggtgcggcagg cccctggacaagggcttgagtggatgggatggattaatacttacaatgggaacacaaactatgcacagaaactccagggcagagtaaccat gactactgacacatccacgaccacagcctacatggagctgaggagcttacgatctgatgacacggccgtttattactgtgcgcgcgtcgctgt aggctattgcagtggtggcagctgctactacttcgattactggggccagggaacattggtcaccgtcagttcaGGAGGCGGTGGT
TCAGGTGGACAACACCATCACCACCATCATGGCGCAGAACAAAAACTCATCTCAGAA GAGGATCTGGGTAGTGGCAAGCCGATCCCGAATCCTCTGCTGGGATTAGACTCCACA TCTTAA (SEQ ID NO: 10)
[68] Anti-SARS-CoV-2 antibody 3388 can have a variable region comprised of a heavy chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHWVR QAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC
AREGNIVATISLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK KVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK FNWYVDGVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CI<VSNI<ALPAP IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
KTTPPVLD SDGSFFL YSKLTVDKSRWQQGNVF SC S VMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11)
This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of:
ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT CGCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATGCTATGCACTGGGTCCG CCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAAGTAA
TAAATACTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAA GAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTA CTGTGCGAGAGAAGGGAATATAGTGGCTACGATTTCTCTGGACTACTGGGGCCAGGG AACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCA
CCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGAC TACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGA CCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGC
CCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCAC ACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCC
CCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGG TGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCG TGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTAC CGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTAC AAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA
GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGA CATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGC CTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAA
GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCA CAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 12) Anti-SARS-CoV-2 antibody 3388 can have a variable region comprised of a light chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSQSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQ LPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSVVF GGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKA
GVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 13)
This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT CGCAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCA CCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGT ACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTCATCTATGGTAACAGCAATCGGC
CCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGC
CATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAG CAGCCTGAGTGTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTCAGCCCAA GGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAG GCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGG
AAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACA
AAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGA AGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAG ACAGTGGCCCCTACAGAATGTTCATAG (SEQ ID NO: 14)
[69] Anti-SARS-CoV-2 antibody 3396 can have a variable region comprised of a heavy chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSGVQLVESGGGLVQPGRSLRVSCAASGFTFADYAMHWVR QAPGKGLEWVSGISWNSGNIAYADSVKGRFTISRDNAKNSLYLQMDSLRPDDTALYYCV KASTLYYYFYMDVWGKGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD
KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV I<FNWYVDGVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CI<VSNI<ALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 15)
This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of:
ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT CGGGAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGA GAGTCTCCTGTGCAGCCTCTGGATTCACCTTTGCTGATTACGCCATGCACTGGGTCCG GCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGAATCAGTTGGAATAGTGGTA
ACATAGCCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCA AGAACTCCCTGTATCTTCAAATGGACAGTCTGAGACCTGATGACACGGCCCTGTATT
ATTGTGTAAAGGCCTCAACCCTCTACTACTATTTCTACATGGATGTCTGGGGCAAAGG GACCACGGTCACCGTTTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCA CCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGAC TACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGA
CCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGC CCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCAC ACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCC CCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGG TGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCG
TGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTAC CGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTAC AAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGA CATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGC CTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAA GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCA CAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 16) Anti-SARS-CoV-2 antibody 3396 can have a variable region comprised of a light chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSQSALTQPPSASGSPGQSVTISCTGTSSDVGGYDYVSWYQQ HPGKAPKFMIYEVSKRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCCSYAGSNNY VFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPV KAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 17)
This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT CGCAGTCTGCCCTGACTCAGCCTCCCTCCGCGTCCGGGTCTCCTGGACAGTCAGTCAC CATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATGACTATGTCTCCTGGTAC CAACAGCACCCAGGCAAAGCCCCCAAATTCATGATTTATGAGGTCAGTAAGCGGCCC
TCAGGGGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCG TCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCTGCTCATATGCAGGCA GCAACAATTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTAGGTCAGCCCAAGG
CTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGC CACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAA GGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAA GCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAG TCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGAC AGTGGCCCCTACAGAATGTTCATAG (SEQ ID NO: 18)
[70] Anti-SARS-CoV-2 antibody 3908 can have a variable region comprised of a heavy chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSEVQLVESRGGLVQPGGSLRLSCAATGFTLSSFDMHWVRQ ATGKGLEWVSAIGTAGDTYYPGSVKGRFTISRENAKNSLYLQMNSLRAGDTAVYYCAR GTWLRDYNFWSGYNYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK PSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK (SEQ ID NO: 19)
This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of: ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT CGGAGGTGCAGCTGGTGGAGTCTAGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGA GACTCTCCTGTGCAGCCACTGGATTCACCCTCAGTAGCTTCGACATGCACTGGGTCCG CCAAGCTACAGGAAAAGGTCTGGAGTGGGTCTCAGCTATTGGTACTGCTGGTGACAC ATACTATCCAGGCTCCGTGAAGGGCCGATTCACCATCTCCAGAGAAAATGCCAAGAA CTCCTTGTATCTTCAAATGAACAGCCTGAGAGCCGGGGACACGGCTGTGTATTACTGT GCAAGAGGGACCTGGCTCCGAGATTACAATTTTTGGAGTGGTTATAATTACTACTTTG ACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCAT CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGG GCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCG CCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTC CCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTG CAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAAT CTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGAC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAA
CTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGC
AGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGC
TGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCG
AGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTG
CCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA
GGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAA
CAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGC
AAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTG
ATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT
AAATGA (SEQ ID NO: 20)
Anti-SARS-CoV-2 antibody 3908 can have a variable region comprised of a light chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSQSALTQPPSASGSPGQSVTISCTGTSSDVGGYIYVSWYQQ
HPGKAPKLIIYEVSKRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYADSNNYV
FGSGTRVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVK
AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 21)
This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT
CGCAGTCTGCCCTGACTCAGCCTCCCTCCGCGTCCGGGTCTCCTGGACAGTCAGTCAC
CATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATATCTATGTCTCCTGGTAC
CAACAACACCCAGGCAAAGCCCCCAAACTCATCATTTATGAGGTCAGTAAGCGGCCC
TCAGGGGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCG
TCTCTGGGCTCCAGGCTGAAGATGAGGCTGATTATTATTGCAGCTCATATGCAGACA
GCAACAATTATGTCTTCGGAAGTGGGACCAGGGTCACCGTCCTAGGTCAGCCCAAGG
CTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGC
CACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAA
GGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAA
GCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAG
TCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGAC
AGTGGCCCCTACAGAATGTTCATAG (SEQ ID NO: 22)
[71] Anti-SARS-CoV-2 antibody 3916 can have a variable region comprised of a heavy chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSQVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIR QPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARQ RGQRITMVRLKRDWFDPWGQGTL VTVS S ASTKGPS VFPL APS SKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG K (SEQ ID NO: 23)
This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of: ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT CGCAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAGCTGGATCCG CCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGGAAATCAATCATAGTGGAAGCA CCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGA ACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCTGTGTATTACTG TGCGAGGCAAAGGGGGCAACGTATTACTATGGTTCGGCTAAAACGGGACTGGTTCGA
CCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATC GGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGG CTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC CCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGC AACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACC GTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCT GAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAAC TGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCA GTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCT GAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGA GAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC CCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAG GCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAAC AACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCA AGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGA
TGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTA AATGA (SEQ ID NO: 24)
Anti-SARS-CoV-2 antibody 3916 can have a variable region comprised of a light chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSQSVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLP GTAPKLLIYSNNQRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGPVF GGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKA GVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 25)
This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT CGCAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCA CCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAAGTAATACTGTAAACTGGTACC AGCAGCTCCCAGGAACGGCCCCCAAACTCCTCATCTATAGTAATAATCAGCGGCCCT CAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCAT CAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAG CCTGAATGGTCCTGTATTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTCAGCCCAA GGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAG GCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGG AAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACA AAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGA AGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAG ACAGTGGCCCCTACAGAATGTTCATAG (SEQ ID NO: 26)
[72] Anti-SARS-CoV-2 antibody 3929 can have a variable region comprised of a heavy chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSQVQLVQSGAEVMTVGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWINTYNGNTNYAQKLQGRVTMTTDTSTTTAYMELRSLRSDDTAVYY CARVAVGYCSGGSCYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KD YFPEP VT VSWNSGALTSGVHTFP AVLQS SGL YSLS S VVTVPS S SLGTQT YICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVI<FNWYVDGVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CI<VS NKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK (SEQ ID NO: 27)
This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of: ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT
CGCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGATGACAGTGGGGGCCTCAGTGA
AGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAGCTATGGTATCAGCTGGGTGCG
ACAGGCCCCCGGACAAGGGCTTGAGTGGATGGGATGGATCAACACTTACAATGGTA
ACACAAACTATGCACAGAAGCTCCAGGGCAGAGTCACCATGACCACAGACACATCC
ACGACCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTAT
TACTGTGCGAGAGTCGCTGTAGGATATTGCAGTGGTGGTAGCTGCTACTACTTTGACT
ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGG
TCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCT
GCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC
TGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCT
CAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAA
CGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTT
GTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGT
CAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA
GGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTG
GTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGT
ACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGA
AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCC
CATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCT
TCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAAC
TACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGC
TCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGC
ATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAT
GA (SEQ ID NO: 28)
Anti-SARS-CoV-2 antibody 3929 can have a variable region comprised of a light chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSQSVLTQPPSASGTPGQRVTISCSGSSSNMGSNFVYWYQHL
PGTAPKLLIQRNNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGVV
FGGGTALTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVK
AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 29)
This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT
CGCAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCA
CCATCTCTTGTTCTGGAAGCAGTTCCAATATGGGAAGTAATTTTGTATACTGGTACCA
GCACCTCCCAGGAACGGCCCCCAAACTCCTCATCCAAAGAAATAATCAGCGGCCCTC
AGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATC
AGTGGGCTCCGGTCCGAGGATGAGGCTGATTACTACTGTGCAGCATGGGATGACAGC
CTGAATGGTGTGGTCTTCGGCGGAGGGACCGCGCTGACCGTCCTAGGTCAGCCCAAG
GCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGG
CCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGA
AGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAA
AGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAA
GTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGA
CAGTGGCCCCTACAGAATGTTCATAG (SEQ ID NO: 30)
[73] Anti-SARS-CoV-2 antibody 3940 can have a variable region comprised of a heavy chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSEVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQ
MPGKGLEWMGIIYPGDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCAR
GDCSSTSCYLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV
TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK
VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF
NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI
EKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK
TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ
ID NO: 31)
This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of:
ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT
CGGAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTG
AAGATCTCCTGTAAGGGTTCTGGATACAGCTTTACCAGCTACTGGATCGGCTGGGTG
CGCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGGGATCATCTATCCTGGTGACTCT
GATACCAGATACAGCCCGTCCTTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCC
ATCAGCACCGCCTACCTGCAGTGGAGCAGCCTGAAGGCCTCGGACACCGCCATGTAT
TACTGTGCGAGGGGCGATTGTAGTAGTACCAGCTGCTACCTTGACTACTGGGGCCAG
GGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGG
CACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG
ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCG
TGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGT
GACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAA
GCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTC
ACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTT
CCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGT
GGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACG
GCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACG
TACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAG
TACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCC
AAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGA
GGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAG
CGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA
CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGA CAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCT GCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO:
32)
Anti-SARS-CoV-2 antibody 3940 can have a variable region comprised of a light chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSHSEQNRQRAGRERAERRVNISGAGSSTKKGTGNDVPWY QQPPDTAPKLMIYEVSNRPSGVPDRFSGSKSGTTASLTISGLQAEDEADYYCGLYPSSTVV FGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 33)
This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT
CGCACTCTGAGCAGAATCGGCAGCGCGCCGGGAGGGAAAGAGCGGAGCGAAGGGTG
AACATCTCCGGCGCTGGGAGCAGCACAAAAAAAGGAACAGGTAACGATGTCCCCTG
GTACCAGCAGCCCCCAGACACAGCCCCCAAACTCATGATTTATGAGGTCAGTAATCG GCCCTCAGGGGTCCCTGATCGCTTCTCGGGGTCCAAGTCTGGCACCACGGCCTCCCTG ACCATCTCGGGGCTGCAGGCTGAGGACGAGGCCGATTATTACTGCGGCTTGTATCCA
AGTAGTACTGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAG GCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGG
CCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGA AGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAA AGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAA GTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGA CAGTGGCCCCTACAGAATGTTCATAG (SEQ ID NO: 34)
[74] Anti-SARS-CoV-2 antibody 4021 can have a variable region comprised of a heavy chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSEVQLVESGGGLVQAGGSLRLSCAASGFSFSSTYMSWVRQ APERGLEWVSNIYTDGAAHYTDSVKGRFTISRDNSKNTLYLQMESLRPEDTAVYYCTKV ITGYSSGWRPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK
KVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK FNWYVDGVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CI<VSNI<ALPAP IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLD SDGSFFL YSKLTVDKSRWQQGNVF SC S VMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 35)
This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of: ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT
CGGAGGTGCAACTGGTGGAGTCTGGGGGAGGCTTGGTCCAGGCTGGGGGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGTAGCACCTATATGAGTTGGGTCCG CCAGGCTCCAGAGAGGGGGCTGGAGTGGGTTTCAAATATTTATACCGATGGTGCGGC ACACTACACAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAA CACGCTGTACCTTCAAATGGAAAGCCTGCGACCTGAGGACACGGCTGTGTATTACTG
TACGAAAGTTATCACCGGGTACAGCAGTGGCTGGCGCCCATTTGACTACTGGGGCCA GGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTG GCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG GACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGG
TGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACA AGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCT TCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCG TGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACG
GCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACG
TACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAG
TACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCC
AAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGA
GGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAG
CGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA
CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGA
CAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCT
GCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 36)
Anti-SARS-CoV-2 antibody 4021 can have a variable region comprised of a light chain with the amino acid sequence of:
MYRMQLLSCIALSLALVTNSQSALTQPASVSGSPGLSITISCTGTSGDVGSYKSVSWYQQ
HPGKAPKLIIYDVNKRPSGVSDRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSTNTLFG
GGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKA
GVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 37)
This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATT
CGCAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACTGTCGATCAC
CATCTCCTGCACTGGAACCAGCGGCGACGTTGGTAGTTATAAGTCTGTCTCCTGGTAC
CAACAACACCCAGGCAAAGCCCCCAAACTCATCATTTATGATGTCAATAAGCGGCCC
TCAGGGGTGTCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCA
TCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATACACAAGCA
CCAACACTTTATTCGGCGGAGGGACCAAGGTGACCGTCCTGGGTCAGCCCAAGGCTG
CCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCAC
ACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGC
AGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCA
ACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCC
ACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG
GCCCCTACAGAATGTTCATAG (SEQ ID NO: 38)
[75] SC2 antibody 3417 binds to Sino CoV2 SI (spike protein 1), NAC CoV2 SI, Sino CoV2
S2 (spike protein 2) (Ka = 63 nM - Carterra LSA), Sino CoV2 SI + S2, and Sino CoV2 RBD (Receptor Binding Domain) (Ka = 7.2 nM - Carterra LSA; Ka < 1 pM ForteBio). SC2 antibody 3387 binds to SI and RBD. SC2 antibody 3388 binds to NAC CoV2 SI, Sino CoV2 S2 (Kd = 10
nM - Carterra LSA), Sino CoV2 RBD (Kd < 1 pM - ForteBio), ProteinTech CoV2 Membrane Protein, ProteinTech CoV2 Nucleocapsid, and NAC Cov2 Mosaic. SC2 antibody 3388 also cross reacts with SARS1 SI and SARS1 RBD. SC2 antibody 3396 binds to Sino CoV2 S2 (Ka = 122nM - ForteBio), Sino CoV2 RBD (Kd = 22nM - ForteBio), and NAC CoV2 Mosaic (Kd = 21 nM - ForteBio). SC2 antibody 3908 binds to Sino CoV2 SI, NAC CoV2 SI, Sino CoV2 S2 (Kd = 74 nM - ForteBio), Sino CoV2 RBD, NAC CoV2 Mosaic, and ProteinTech CoV2 Nucleocapsid. SC2 antibody 3908 also cross reacts with Coll SARS1 S1+S2 and Coll SARS1 RBD. SC2 antibody 3916 binds to NAC CoV2 SI, Sino CoV2 S2, Sino CoV2 S1+S2, Sino CoV2 RBD, NAC CoV2 Mosaic, ProteinTech Membrane Protein and ProteinTech Nucleocapsid. SC2 antibody 3916 also cross reacts with Coll SARS1 S1+S2 and Coll SARS1 RBD. SC2 antibody 3929 binds to Sino CoV2 RBD. SC2 antibody 3940 binds to Sino SARS1 SI (Kd = 15 nM - Carterra LSA), HKU1 S1+S2 (Kd = 17 nM - Carterra LSA), Sino CoV2 SI, NAC CoV2 SI, and Sino CoV2 RBD. SC2 antibody 3388 binds to NAC CoV2 SI, Sino CoV2 S2 (Kd = 10 nM - Carterra LSA), Sino CoV2 RBD (Kd < 1 pM - ForteBio), NAC COV2 Mosaic, ProteinTech Membrane Protein, and ProteinTech Nucleocapsid. SC2 antibody 3388 also cross reacts with Sino SARS1 SI and Coll SARS1 RBD. SC2 antibody 3705 NAC CoV2 SI (Kd = 57 nM), Sino CoV2 SI, Sino CoV2 S1+S2, and Sino CoV2 RBD (Kd = 1.3 nM).
[76] The anti-SARS-CoV-2 antibodies 3417 (SEQ ID NO: 1 and 3), 3387 (SEQ ID NO: 5 and 7), 3388 (SEQ ID NO: 11 and 13), 3396 (SEQ ID NO: 15 and 17), 3908 (SEQ ID NO: 19 and 21), 3916 (SEQ ID NO: 23 and 25), 3929 (SEQ ID NO: 27 and 29), 3940 (SEQ ID NO: 31 and 33), 4021 (SEQ ID NO: 35 and 37), and 3705 (SEQ ID NO: 9) also include variable regions having amino acid sequences that have 99%, 95%, 90%, 80% or 70% sequence identity with one of the heavy chains from variable region SEQ ID NO: 1, 5, 11, 15, 19, 23, 27, 31 or 35, and a light chain that has 99%, 95%, 90%, 80% or 70% sequence identity with one light chains from variable region SEQ ID NO: 3, 7, 13, 17, 21, 25, 29, 33, or 37.
[77] CDRs from anti-SARS-CoV-2 antibodies 3417 (SEQ ID NO: 1 and 3), 3387 (SEQ ID NO: 5 and 7), 3388 (SEQ ID NO: 11 and 13), 3396 (SEQ ID NO: 15 and 17), 3908 (SEQ ID NO: 19 and 21), 3916 (SEQ ID NO: 23 and 25), 3929 (SEQ ID NO: 27 and 29), 3940 (SEQ ID NO: 31 and 33), 4021 (SEQ ID NO: 35 and 37), and 3705 (SEQ ID NO: 9) can be use to make CDR grafted antibodies known in the art.
[78] The CDRs of SC2 antibody 3417 are:
GGTGTCTCCATCAGAAATAGTAATTACTTC heavy chain CDR1 (SEQ ID NO: 39) ATGCATAGTGGTGGGACCACC heavy chain CDR2 (SEQ ID NO: 40)
GCGAGAGATGACCCCCTTAACCGGTTCGCTGCTTTTCAAATC heavy chain CDR3 (SEQ ID NO: 41)
AGCTCCAACATTGGGAATAAATAT light chain CDR1 (SEQ ID NO: 42)
GACAATAAT light chain CDR2 (SEQ ID NO: 43)
GGAACATGGGATAGCAGCCTGAGTGTTTTTTATGTC light chain CDR3 (SEQ ID NO: 44)
The CDRs of SC2 antibody 3387 are:
GGTTACACCTTTACCAGCTATGGT heavy chain CDR1 (SEQ ID NO: 45)
ATCAACACTTACAATGGTAACACA heavy chain CDR2 (SEQ ID NO: 46)
GCGAGAGTCGCTGTAGGATATTGCAGTGGTGGTAGCTGCTACTACTTTGACTAC heavy chain CDR3 (SEQ ID NO: 47)
CAGAGTGTTAGCAACAAC light chain CDR1 (SEQ ID NO: 48)
GGTGCATCC light chain CDR2 (SEQ ID NO: 49)
CAGCAGTATAATGACTGGCCTCCGTCTTGGACG light chain CDR3 (SEQ ID NO: 50)
The CDRs of SC2 antibody 3388 are:
GGATTCACCTTCAGTAGCTATGCT heavy chain CDR1 (SEQ ID NO: 51)
ATATCATATGATGGAAGTAATAAA heavy chain CDR2 (SEQ ID NO: 52)
GCGAGAGAAGGGAATATAGTGGCTACGATTTCTCTGGACTAC heavy chain CDR3 (SEQ ID NO: 53)
AGCTCCAACATCGGGGCAGGTTATGAT light chain CDR1 (SEQ ID NO: 54)
GGTAACAGC light chain CDR2 (SEQ ID NO: 55)
CAGTCCTATGACAGCAGCCTGAGTGTGGTA light chain CDR3 (SEQ ID NO: 56)
The CDRs of SC2 antibody 3396 are:
GGATTCACCTTTGCTGATTACGCC heavy chain CDR1 (SEQ ID NO: 57)
ATCAGTTGGAATAGTGGTAACATA heavy chain CDR2 (SEQ ID NO: 58)
GTAAAGGCCTCAACCCTCTACTACTATTTCTACATGGATGTC heavy chain CDR3 (SEQ ID NO: 59)
AGCAGTGACGTTGGTGGTTATGACTAT light chain CDR1 (SEQ ID NO: 60)
GAGGTCAGT light chain CDR2 (SEQ ID NO: 61)
TGCTCATATGCAGGCAGCAACAATTATGTC light chain CDR3 (SEQ ID NO: 62)
The CDRs of SC2 antibody 3908 are:
GGATTCACCCTCAGTAGCTTCGAC heavy chain CDR1 (SEQ ID NO: 63)
ATTGGTACTGCTGGTGACACA heavy chain CDR2 (SEQ ID NO: 64)
GCAAGAGGGACCTGGCTCCGAGATTACAATTTTTGGAGTGGTTATAATTACTACTTTG
ACT AC heavy chain CDR3 (SEQ ID NO: 65)
AGCAGTGACGTTGGTGGTTATATCTAT light chain CDR1 (SEQ ID NO: 66)
GAGGTCAGT light chain CDR2 (SEQ ID NO: 67)
AGCTCATATGCAGACAGCAACAATTATGTC light chain CDR3 (SEQ ID NO: 68)
The CDRs of SC2 antibody 3916 are:
GGTGGGTCCTTCAGTGGTTACTAC heavy chain CDR1 (SEQ ID NO: 69)
ATCAATCATAGTGGAAGCACC heavy chain CDR2 (SEQ ID NO: 70)
GCGAGGCAAAGGGGGCAACGTATTACTATGGTTCGGCTAAAACGGGACTGGTTCGAC
CCC heavy chain CDR3 (SEQ ID NO: 71)
AGCTCCAACATCGGAAGTAATACT light chain CDR1 (SEQ ID NO: 72)
AGTAATAAT light chain CDR2 (SEA ID NO: 73)
GCAGCATGGGATGACAGCCTGAATGGTCCTGTA light chain CDR3 (SEQ ID NO: 74)
The CDRs of SC2 antibody 3929 are:
GGTTACACCTTTACCAGCTATGGT heavy chain CDR1 (SEQ ID NO: 75)
ATCAACACTTACAATGGTAACACA heavy chain CDR2 (SEQ ID NO: 76)
GCGAGAGTCGCTGTAGGATATTGCAGTGGTGGTAGCTGCTACTACTTTGACTAC heavy chain CDR3 (SEQ ID NO: 77)
AGTTCCAATATGGGAAGTAATTTT light chain CDR1 (SEQ ID NO: 78)
AGAAATAAT light chain CDR2 (SEQ ID NO: 79)
GCAGCATGGGATGACAGCCTGAATGGTGTGGTC light chain CDR3 (SEQ ID NO: 80)
The CDRs of SC2 antibody 3940 are:
GGATACAGCTTTACCAGCTACTGG heavy chain CDR1 (SEQ ID NO: 81)
ATCTATCCTGGTGACTCTGATACC heavy chain CDR2 (SEQ ID NO: 82)
GCGAGGGGCGATTGTAGTAGTACCAGCTGCTACCTTGACTAC heavy chain CDR3 (SEQ
ID NO: 83)
AGCACAAAAAAAGGAACAGGTAACGAT light chain CDR1 (SEQ ID NO: 84)
GAGGTCAGT light chain CDR2 (SEQ ID NO: 85)
GGCTTGTATCCAAGTAGTACTGTGGTT light chain CDR3 (SEQ ID NO: 86)
The CDRs of SC2 antibody 4021 are:
GGATTCAGCTTCAGTAGCACCTAT heavy chain CDR1 (SEQ ID NO: 87)
ATTTATACCGATGGTGCGGCA heavy chain CDR2 (SEQ ID NO: 88)
ACGAAAGTTATCACCGGGTACAGCAGTGGCTGGCGCCCATTTGACTAC heavy chain
CDR3 (SEQ ID NO: 89)
AGCGGCGACGTTGGTAGTTATAAGTCT light chain CDR1 (SEQ ID NO: 90)
GATGTCAAT light chain CDR2 (SEQ ID NO: 91)
AGCTCATACACAAGCACCAACACTTTA light chain CDR3 (SEQ ID NO: 92)
The CDRs of SC2 antibody 3705 are:
GGTTATACCTTTACCAGCTATGGA heavy chain CDR1 (SEQ ID NO: 93) ATTAATACTTACAATGGGAACACA heavy chain CDR2 (SEQ ID NO: 94) GCGCGCGTCGCTGTAGGCTATTGCAGTGGTGGCAGCTGCTACTACTTCGATTAC heavy chain CDR3 (SEQ ID NO: 95)
CAGAGTGTTAGCAACAAC light chain CDR1 (SEQ ID NO: 96) GGTGCATCC light chain CDR2 (SEQ ID NO: 97) CAGCAGTATAATGACTGGCCTCCGTCTTGGACG light chain CDR3 (SEQ ID NO: 98)
[79] An anti-SARS-CoV-2 antibody can also include a variable region made from a nucleic acid encoding a heavy chain that has 99%, 95%, 90%, 80% or 70% sequence identity with one of the nucleic acids encoding a heavy chain (SEQ ID NO: 2, 6, 12, 16, 20, 24, 28, 32, or 36), and a nucleic acid encoding a light chain that has 99%, 95%, 90%, 80% or 70% sequence identity with one of the nucleic acids encoding a light chain (SEQ ID NO: 4, 8, 14, 18, 22, 26, 30, 34, or 38). An anti- SARS-CoV-2 antibody can also include a variable region made from a nucleic acid encoding a heavy chain that hybridizes under stringent hybridization conditions with one of the nucleic acids encoding one of the heavy chains (SEQ ID NO: 2, 6, 12, 16, 20, 24, 28, 32 or 36), and a nucleic acid encoding a light chain that hybridizes under stringent hybridization conditions with one of the nucleic acids encoding one of the light chains (SEQ ID NO: 4, 8, 14, 18, 22, 26, 30, 34, or 38).
[80] An anti-SARS-CoV-2 antibody can be made with a variable region selected from variable regions encoded by antibodies 1-402. (See Table 1) The heavy chains are encoded by the odd numbered SEQ ID Nos. and the light chains are encoded by the even numbered SEQ ID NOs of each variable region pair. The identifier for each anti-SARS-CoV-2 variable region is in second column labeled Ab, so anti-SARS-CoV-2 variable region (1) is encoded by SEQ ID Nos: 159 (heavy chain) and 160 (light chain), anti-SARS-CoV-2 variable region (2) is encoded by SEQ ID Nos: 161 (heavy chain) and 162 (light chain), anti-SARS-CoV-2 variable region (3) is encoded by SEQ ID Nos: 163 (heavy chain) and 164 (light chain), etc.
[81] Anti-SARS-CoV-2 antibody 3910 can have a variable region comprised of a heavy chain with the amino acid sequence of:
QVQLQESGSGLVKPSQTLSLTCAVSGVSMSTGDYSWSWIRRPPGKGLEWIGYIFLGGRTY SNPSLKSRVTMSIDRSKNQFSLKLTSVTAADTAVYYCARDRSGSGTLDYWGQGTLIAVSS (SEQ ID NO: 99)
This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of:
CAAGTGCAGCTGCAGGAGTCCGGCTCCGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCACCTGCGCTGTCTCTGGTGTCTCCATGAGCACTGGTGATTACTCCTGGAGCTGGA TCCGGCGGCCACCAGGGAAGGGCCTGGAGTGGATTGGTTACATCTTCCTAGGTGGGA
GAACCTACTCCAACCCGTCCCTCAAGAGTCGAGTCACAATGTCAATAGACAGGTCCA
AGAACCAGTTCTCCCTGAAGCTGACCTCTGTGACCGCCGCGGACACGGCCGTATATT
ACTGTGCCAGAGATCGCTCTGGTTCGGGGACCCTTGACTACTGGGGCCAGGGAACCC
TGATCGCCGTCTCCTCA (SEQ ID NO: 100)
Anti-SARS-CoV-2 antibody 3910 can have a variable region comprised of a light chain with the amino acid sequence of:
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVSNRPSGV SNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLFGGGTKLTVL (SEQ ID NO: 101) This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCA
TCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATAACTATGTCTCCTGGTACCA
ACAGCACCCAGGCAAAGCCCCCAAACTCATGATTTATGAGGTCAGTAATCGGCCCTC
AGGGGTTTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATC
TCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATACAAGCAGC
AGCACTCTATTCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 102)
The CDRs of SC2 antibody 3910 are:
GGTGTCTCCATGAGCACTGGTGATTACTCC heavy chain CDR1 (SEQ ID NO: 103)
ATCTTCCTAGGTGGGAGAACC heavy chain CDR2 (SEQ ID NO: 104)
GCCAGAGATCGCTCTGGTTCGGGGACCCTTGACTAC heavy chain CDR3 (SEQ ID NO: 105)
AGCAGTGACGTTGGTGGTTATAACTAT light chain CDR1 (SEQ ID NO: 106)
GAGGTCAGT light chain CDR2 (SEQ ID NO: 107)
AGCTCATATACAAGCAGCAGCACTCTA light chain CDR3 (SEQ ID NO: 108)
[82] Anti-SARS-CoV-2 antibody 3915 can have a variable region comprised of a heavy chain with the amino acid sequence of:
EEQLLESGGDLVWPGGSLRLSCAASGLTFSSYSTNWVRQAPGRGLEWVASISSTSWSRY
YADSVKGRFTISRDNAKNSLYLQMNSLGVEDTAVYYCTADQRARNTGVIDYWGRGTLV TVSS (SEQ ID NO: 109)
This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of:
GAGGAGCAGCTGTTGGAGTCTGGGGGAGACCTGGTCTGGCCTGGGGGGTCCCTGAGA
CTCTCCTGTGCAGCCTCTGGACTCACCTTCAGTAGCTATAGCACGAACTGGGTCCGCC
AGGCTCCAGGGAGGGGGCTGGAGTGGGTCGCGTCCATTAGTAGTACTAGTTGGTCCA GATATTACGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGA ACTCGCTGTATCTGCAAATGAACAGCCTGGGAGTCGAGGATACGGCTGTGTATTACT GTACGGCAGATCAGAGAGCTCGAAACACGGGGGTCATTGACTATTGGGGCCGGGGA
ACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 110)
Anti-SARS-CoV-2 antibody 3915 can have a variable region comprised of a light chain with the amino acid sequence of:
QSALTQPASVSGSPGQSITISCTGTSSDIGGYDYVSWYRQDPGKAPRLMIYEVSNRPSGVS NRFSGAKSGNTASLTISGLQAEDEADYYCSSYSSTSTSVVFGGGTKLTVL (SEQ ID NO: H l)
This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCA TCTCCTGCACTGGAACCAGCAGTGACATTGGTGGTTATGACTATGTCTCGTGGTACCG ACAGGACCCAGGCAAGGCCCCCAGACTCATGATTTATGAGGTCAGTAACCGGCCCTC
AGGGGTTTCTAATCGCTTCTCTGGCGCCAAGTCTGGCAACACGGCCTCCCTGACCATC TCTGGCCTCCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATTCAAGCACC AGCACCTCTGTGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 112)
The CDRs of SC2 antibody 3915 are:
GGACTCACCTTCAGTAGCTATAGC heavy chain CDR1 (SEQ ID NO: 113)
ATTAGTAGTACTAGTTGGTCCAGA heavy chain CDR2 (SEQ ID NO: 114)
ACGGCAGATCAGAGAGCTCGAAACACGGGGGTCATTGACTAT heavy chain CDR3 (SEQ ID NO: 115)
AGCAGTGACATTGGTGGTTATGACTAT light chain CDR1 (SEQ ID NO: 116)
GAGGTCAGT light chain CDR2 (SEQ ID NO: 117)
AGCTCATATTCAAGCACCAGCACCTCTGTGGTG light chain CDR3 (SEQ ID NO: 118) [83] Anti-SARS-CoV-2 antibody 3945 can have a variable region comprised of a heavy chain with the amino acid sequence of:
QLQLQESGSGLVKPSQTLSLTCAVSGGSVSSGGYSWSWIRQPPGKGLEWIGYIYDSGITSY
NPSLKSRLTISIDRSKNQFSLGLSSVTAADTAVYYCARVRRNTSGSFSTGHFDYWGQGTL VTVSS (SEQ ID NO: 119)
This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of:
CAGCTGCAGCTGCAGGAGTCCGGCTCAGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCACCTGCGCTGTCTCTGGTGGCTCCGTCAGCAGTGGTGGTTATTCCTGGAGCTGGA TCCGGCAGCCACCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATGATAGTGGGA
TCACCTCCTACAACCCGTCCCTCAAGAGCCGACTCACCATATCAATAGACAGGTCCA AGAACCAGTTCTCCCTGGGGCTGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATT ACTGTGCCAGAGTTCGGCGGAATACTAGTGGTTCTTTCTCGACCGGCCACTTTGACTA CTGGGGCCAGGGAACCCTAGTCACCGTCTCCTCA (SEQ ID NO: 120)
Anti-SARS-CoV-2 antibody 3945 can have a variable region comprised of a light chain with the amino acid sequence of:
QSALTQPASVSGSPGQSITISCTGTSSDVGAYNYVSWYQHHPGKAPKLMIYDVSDRPSGV SNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTNTSTLYVFGTGTKVTVL (SEQ ID NO: 121)
This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
CAGTCTGCCCTGACTCAGCCTGCCTCCGTATCTGGGTCTCCTGGACAGTCGATCACCA TCTCCTGCACTGGAACCAGCAGTGACGTTGGTGCTTATAACTATGTCTCTTGGTACCA ACACCACCCAGGCAAAGCCCCCAAACTCATGATTTATGATGTCAGTGATCGGCCCTC
AGGAGTTTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATC TCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATACAAACACC AGCACTCTTTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA (SEQ ID NO: 122)
The CDRs of SC2 antibody 3945 are:
GGTGGCTCCGTCAGCAGTGGTGGTTATTCC heavy chain CDR1 (SEQ ID NO: 123)
ATCTATGATAGTGGGATCACC heavy chain CDR2 (SEQ ID NO: 124)
GCCAGAGTTCGGCGGAATACTAGTGGTTCTTTCTCGACCGGCCACTTTGACTAC heavy chain CDR3 (SEQ ID NO: 125)
AGCAGTGACGTTGGTGCTTATAACTAT light chain CDR1 (SEQ ID NO: 126)
GATGTCAGT light chain CDR2 (SEQ ID NO: 127)
AGCTCATATACAAACACCAGCACTCTTTATGTC light chain CDR3 (SEQ ID NO: 128) [84] Anti-SARS-CoV-2 antibody 3947 can have a variable region comprised of a heavy chain with the amino acid sequence of:
QLQLQESGSGLVKPSQTLSLTCAVSGGSVSSGGYSWSWIRQPPGKGLEWIGYIYDSGITSY
NPSLKSRLTISIDRSKNQFSLGLSSVTAADTAVYYCARVRRNTSGSFSTGHFDYWGQGTL
VTVSS (SEQ ID NO: 129)
This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of: CAGCTGCAGCTGCAGGAGTCCGGCTCAGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCACCTGCGCTGTCTCTGGTGGCTCCGTCAGCAGTGGTGGTTATTCCTGGAGCTGGA
TCCGGCAGCCACCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATGATAGTGGGA TCACCTCCTACAACCCGTCCCTCAAGAGCCGACTCACCATATCAATAGACAGGTCCA
AGAACCAGTTCTCCCTGGGGCTGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATT ACTGTGCCAGAGTTCGGCGGAATACTAGTGGTTCTTTCTCGACCGGCCACTTTGACTA
CTGGGGCCAGGGAACCCTAGTCACCGTCTCCTCA (SEQ ID NO: 130)
Anti-SARS-CoV-2 antibody 3947 can have a variable region comprised of a light chain with the amino acid sequence of:
QSVLTQPPSVSASPGQTVTISCSGSTSNIGGNYVSWYQHLPGTAPKLLIYDSNKRPSGIPDR
FSGSKSGTSATLGITGLQTEDEADYYCGTWDYRLSGAVFGGGTKLTVL (SEQ ID NO: 131) This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGCGTCCCCAGGACAAACGGTCACC
ATCTCCTGCTCTGGAAGCACCTCCAACATTGGTGGTAATTATGTCTCCTGGTACCAGC
ACCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAGTAATAAGCGACCCTCAG
GGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCAC
CGGACTCCAGACTGAGGATGAGGCCGATTATTACTGTGGAACATGGGATTACAGACT
GAGTGGTGCGGTCTTCGGAGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 132)
The CDRs of SC2 antibody 3947 are:
GGTGGCTCCGTCAGCAGTGGTGGTTATTCC heavy chain CDR1 (SEQ ID NO: 133)
ATCTATGATAGTGGGATCACC heavy chain CDR2 (SEQ ID NO: 134)
GCCAGAGTTCGGCGGAATACTAGTGGTTCTTTCTCGACCGGCCACTTTGACTAC heavy chain CDR3 (SEQ ID NO: 135)
ACCTCCAACATTGGTGGTAATTAT light chain CDR1 (SEQ ID NO: 136)
GGAACATGGGATTACAGACTGAGTGGTGCGGTCGACAGTAAT light chain CDR2 (SEQ ID NO: 137) light chain CDR3 (SEQ ID NO: 138)
[85] Anti-SARS-CoV-2 antibody 3969 can have a variable region comprised of a heavy chain with the amino acid sequence of:
Q VQLVESGGGVVQPGRSLRLSC AASGFTF S S YGMHWVRQ APGKGLEW VAVIS YDGSNK
YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGVGDYAVWGQGTLVTVS
S (SEQ ID NO: 139)
This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of:
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG
ACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGC
CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAAGTAAT
AAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAG
AACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTAC
TGTGCGAAAGGAGTGGGTGACTACGCGGTCTGGGGCCAGGGAACCCTGGTCACCGTC TCCTCA (SEQ ID NO: 140)
Anti-SARS-CoV-2 antibody 3969 can have a variable region comprised of a light chain with the amino acid sequence of:
QSALTQPASVSGSPGQSITISCTGTNSDIGGYDYVSWYQQHPGKAPKLMIFDVNNRPSGV SNRFSGSKSGNTASLTISELQSADEADYFCSSFSTRNSLVVFGGGTKLTVL (SEQ ID NO: 141)
This light chain amino acid sequence can be encoded in a nucleic acid sequence of:
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCA TCTCCTGCACTGGAACCAACAGTGACATTGGTGGTTATGATTATGTCTCCTGGTACCA ACAACACCCAGGCAAAGCCCCCAAACTCATGATTTTTGACGTCAATAATCGGCCCTC AGGGGTTTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATC TCTGAGCTCCAGTCTGCGGACGAGGCTGATTATTTCTGCAGCTCTTTTTCAACCAGAA ACTCTCTCGTGGTGTTCGGCGGAGGGACCAAACTGACCGTCCTA (SEQ ID NO: 142) The CDRs of SC2 antibody 3969 are:
GGATTCACCTTCAGTAGCTATGGC heavy chain CDR1 (SEQ ID NO: 143)
ATATCATATGATGGAAGTAATAAA heavy chain CDR2 (SEQ ID NO: 144)
GCGAAAGGAGTGGGTGACTACGCGGTC heavy chain CDR3 (SEQ ID NO: 145)
AACAGTGACATTGGTGGTTATGATTAT light chain CDR1 (SEQ ID NO: 146)
GACGTCAAT light chain CDR2 (SEQ ID NO: 147)
AGCTCTTTTTCAACCAGAAACTCTCTCGTGGTG light chain CDR3 (SEQ ID NO: 148) [86] Anti-SARS-CoV-2 antibody 4083 can have a variable region comprised of a heavy chain with the amino acid sequence of:
QLQLQESGSGLVKPSQTLSLTCAVSGGSVSSGGYSWSWIRQPPGKGLEWIGYIYDSGITSY NPSLKSRLTISIDRSKNQFSLGLSSVTAADTAVYYCARVRRNTSGSFSTGHFDYWGQGTL VTVSS (SEQ ID NO: 149)
This heavy chain amino acid sequence can be encoded in a nucleic acid sequence of:
CAGCTGCAGCTGCAGGAGTCCGGCTCAGGACTGGTGAAGCCTTCACAGACCCTGTCC
CTCACCTGCGCTGTCTCTGGTGGCTCCGTCAGCAGTGGTGGTTATTCCTGGAGCTGGA TCCGGCAGCCACCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATGATAGTGGGA TCACCTCCTACAACCCGTCCCTCAAGAGCCGACTCACCATATCAATAGACAGGTCCA AGAACCAGTTCTCCCTGGGGCTGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATT ACTGTGCCAGAGTTCGGCGGAATACTAGTGGTTCTTTCTCGACCGGCCACTTTGACTA CTGGGGCCAGGGAACCCTAGTCACCGTCTCCTCA (SEQ ID NO: 150)
Anti-SARS-CoV-2 antibody 4083 can have a variable region comprised of a light chain with the amino acid sequence of:
QSVLTQPPSVSAVPGQKVTISCSGNNSNIGNNLVSWYQQLPGTAPKLLIYNNNRRPSGIPD RFSGSKSGTSATLGITGLQTGDEAAYYCAARDSSLSAVVFGGGTKLTVL (SEQ ID NO: 151)
This light chain amino acid sequence can be encoded in a nucleic acid sequence of: CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGTCCCAGGACAGAAGGTCACC ATCTCCTGCTCTGGAAACAACTCCAATATTGGAAATAATCTTGTATCCTGGTACCAGC AGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATAACAATAATAGGCGACCATCAG GGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCAC CGGACTCCAGACTGGGGACGAGGCCGCTTATTATTGCGCAGCAAGGGATAGCAGCCT GAGTGCTGTGGTGTTCGGCGGAGGGACCAAACTGACCGTCCTA (SEQ ID NO: 152) The CDRs of SC2 antibody 4083 are:
GGTGGCTCCGTCAGCAGTGGTGGTTATTCC heavy chain CDR1 (SEQ ID NO: 153) ATCTATGATAGTGGGATCACC heavy chain CDR2 (SEQ ID NO: 154) GCCAGAGTTCGGCGGAATACTAGTGGTTCTTTCTCGACCGGCCACTTTGACTAC heavy chain CDR3 (SEQ ID NO: 155)
AACTCCAATATTGGAAATAATCTT light chain CDR1 (SEQ ID NO: 156) AACAATAAT light chain CDR2 (SEQ ID NO: 157) GCAGCAAGGGATAGCAGCCTGAGTGCTGTGGTG light chain CDR3 (SEQ ID NO: 158)
[87] SC2 antibody 3910 binds to Sino CoV2 SI (spike protein 1), NAC CoV2 SI, and Sino CoV2 RBD (Receptor Binding Domain). SC2 antibody 3915 binds to Sino CoV2 SI (spike protein 1), NAC CoV2 SI, Sino CoV2 RBD (Receptor Binding Domain), and NAC CoV2 Mosaic. SC2 antibody 3945 binds to HKU1 S1+S2 (Kd = 11 nM Carterra LSA). SC2 antibody 3947 binds to Sino CoV2 S2 (Kd = 25 nM Carterra LSA) and HKU1 SI + S2 (Kd = 532 nM Carterra LSA). SC2 antibody 3969 binds to Sino SARS1 SI (Kd = 28 nM Carterra LSA), HKU1 SI + S2 (Kd = 12 nM Carterra LSA), and Sino Cov2 RBD (Kd = 105 nM Carterra LSA). SC2 antibody 4083 binds to Sino Cov2 S2 (Kd = 41 nM Carterra LSA).
[88] The anti-SARS-CoV-2 antibodies 3910 (SEQ ID NO: 99 and 101), 3915 (SEQ ID NO: 109 and 111), 3945 (SEQ ID NO: 119 and 121), 3947 (SEQ ID NO: 129 and 131), 3969 (SEQ ID NO: 139 and 141), and 4083 (SEQ ID NO: 149 and 151) also include variable regions having amino acid sequences that have 99%, 95%, 90%, 80% or 70% sequence identity with one of the heavy chains from variable region SEQ ID NO: 99, 109, 119, 129, 139, or 149, and a light chain that has
99%, 95%, 90%, 80% or 70% sequence identity with one light chains from variable region SEQ ID NO: 101, 11, 121, 131, 141, or 151.
[89] CDRs from anti-SARS-CoV-2 antibodies 3910 (SEQ ID NO: 99 and 101), 3915 (SEQ ID NO: 109 and 111), 3945 (SEQ ID NO: 119 and 121), 3947 (SEQ ID NO: 129 and 131), 3969 (SEQ ID NO: 139 and 141), and 4083 (SEQ ID NO: 149 and 151) can be used to make CDR grafted antibodies known in the art.
[90] An anti-SARS-CoV-2 antibody can also include a variable region made from a nucleic acid encoding a heavy chain that has 99%, 95%, 90%, 80% or 70% sequence identity with one of the nucleic acids encoding a heavy chain (SEQ ID NO: 2, 6, 12, 16, 20, 24, 28, 32, 36, 100, 110, 120, 130, 140, or 150), and a nucleic acid encoding a light chain that has 99%, 95%, 90%, 80% or 70% sequence identity with one of the nucleic acids encoding a light chain (SEQ ID NO: 4, 8, 14, 18, 22, 26, 30, 34, 38, 102, 112, 122, 132, 142, or 152). An anti-SARS-CoV-2 antibody can also include a variable region made from a nucleic acid encoding a heavy chain that hybridizes under stringent hybridization conditions with one of the nucleic acids encoding one of the heavy chains (SEQ ID NO: 2, 6, 12, 16, 20, 24, 28, 32, 36, 100, 110, 120, 130, 140, or 150), and a nucleic acid encoding a light chain that hybridizes under stringent hybridization conditions with one of the nucleic acids encoding one of the light chains (SEQ ID NO: 4, 8, 14, 18, 22, 26, 30, 34, 38, 102, 112, 122, 132, 142, or 152).
[91] An anti-SARS-CoV-2 antibody can also include a variable region (e.g., starting from anti- SARS-CoV-2 variable regions (1) to (402)) made from a nucleic acid encoding a heavy chain that has 99%, 95%, 90%, 80% or 70% sequence identity with one of the heavy chain from variable regions 1-402 (odd numbered SEQ ID Nos), and a nucleic acid encoding a light chain that has 99%, 95%, 90%, 80% or 70% sequence identity with one of the light chain from variable region 1-402 (even numbered SEQ ID NOs). An anti-SARS-CoV-2 antibody can also include a variable region made from a nucleic acid encoding a heavy chain that hybridizes under stringent hybridization conditions with one of the nucleic acids encoding one of the heavy chains from variable regions 903-1706 (odd numbered SEQ ID Nos), and a nucleic acid encoding a light chain that hybridizes under stringent hybridization conditions with one of the nucleic acids encoding one of the light chains from variable regions 903- (even numbered SEQ ID NOs).
[92] The CDRs for the light and heavy chains of the anti-SARS-CoV-2 variable regions 1-402 are known to a person of skill in the art. These CDRs and optionally FR amino acids from the corresponding light or heavy chain can be used to make CDR grafted antibodies as described below.
[93] The anti-SARS-CoV-2 antibodies disclosed herein can bind to SARS-CoV-2 Spike Trimer, SARS-CoV-2 Receptor Binding Domain (RBD), SARS-CoV-2 Membrane Protein (E), and/or
SARS-CoV-2 Nucleocapsid. Antigen specificity for the anti-SARS-CoV-2 variable regions are shown in Table 2. For example, antibodies that bind to SARS-CoV-2 RBD include, for example, anti-SARS-CoV-2 antibodies comprising the anti-SARS-CoV-2 variable region 2-6, 8-22, 24, 29- 34, 35-39, 41-42, 162, 165, 167, 172-173, 177-178, 180, 183-184, 186-187, 192-195, 288, 296, 298-299, 303-304, 313-316, 321-323, 326-328, 332, 334, 337-338, 344-345, 347, 350, 355-356, 358-360, 368-370, 378-380. For example, antibodies that bind to SARS-CoV-2 Spike trimer include, for example, anti-SARS-CoV-2 antibodies comprising the anti-SARS-CoV-2 variable region 1-4, 7, 14-16, 19-20, 31, 37, 162, 171, 186. For example, antibodies that bind to SARS- CoV-2 Membrane Protein include, for example, anti-SARS-CoV-2 antibodies comprising the anti- SARS-CoV-2 variable region 202-209, 218-219, 222-223, 227, 229-231, 242-245, 261, 280. For example, antibodies that bind to SARS-CoV-2 Nucleocapsid include, for example, anti-SARS- CoV-2 antibodies comprising the anti-SARS-CoV-2 variable region 202-209, 214-215, 218-219, 221-223, 227, 229-231, 236, 242-243, 245, 261, 271, 280.
[94] Any of the anti-SARS-CoV-2 antibodies described above can be made from a nucleic acid encoding a full-length antibody that lacks any introns, and so, is non-natural. The non-natural nucleic acids can include the combination of a variable region (e.g., anti-SARS-CoV-2 antibody variable regions 1-451) operably linked to a constant region (e.g., IgGl, IgG2, IgG3, or IgG4) that is non-natural for that variable region. Any of the above nucleic acids can be used to recombinantly make the anti-SARS-CoV-2 antibodies described herein. The anti-SARS-CoV-2 antibodies also include amino acid sequences that are non-natural including the combination of a variable region (e.g., anti-SARS-CoV-2 antibody variable regions 1-451) operably linked to a constant region (e.g., IgGl, IgG2, IgG3, or IgG4) that is non-natural for that variable region.
[95] An anti-SARS-CoV-2 antibody can bind to SARS-CoV-2 with an affinity (Kd) of less than one picomolar. An anti-SARS-CoV-2 antibody can bind with an affinity of at least 1 pM, or at least 10 pM, or at least 100 pM.
[96] The anti-SARS-CoV-2 antibodies disclosed herein can also be used to make chimeric antigen receptors for arming T-cells treat infections from SARS-CoV-2. For example, the antibodies can be formatted into a single chain structure recombinantly combined with appropriate transmembrane and signaling components to make a chimeric antigen receptor.
[97] The anti-SARS-CoV-2 antibodies disclosed herein can have neutralizing activity against SARS-CoV-2 in an in vitro cell infection model. For example, the antibodies SC2 antibody 3417, SC2 antibody 3387, SC2 antibody 3396, and SC2 antibody 3705 neutralized SARS-CoV-2 and blocked the virus from infecting cells. In addition, the SC2 antibody 3387 was able to bind to spike proteins with the mutations D614G and E484K (Sweden-1 variant of European variant B-l), or
D614G,V445I,H655Y,and E583D (England/Bristol variant of European variant B-l), or G485S (related to Australia-1 variant), or N501Y (South African variant Bl.l), or S494P, or V483K, or R683A, R685A, F817P, A892P, A899P, A942P, K986P, V987P. The ability to bind all of these variants shows the broad specificity of these anti-SARS-CoV-2 antibodies.
[98] The anti-SARS-CoV-2 antibodies described herein (e.g., SC2 antibody 3387 or SC2 antibody 3705) can be used in methods to neutralize SARS-CoV-2 and/or for treating CO VID-19 infection so as to reduce at least one symptom associated with COV ID- 19. Compositions comprising at least one isolated recombinant monoclonal antibody that binds specifically to SARS- CoV-2 virus and thereby neutralizes the virus are used in these methods. The anti-SARS-CoV-2 antibody can be administered prophylactically and/or can be administered to patients with COVID- 19 infections.
Nucleic Acids
[99] The disclosure also relates to nucleic acids that encode, at least in part, the individual peptides, polypeptides, and proteins described herein. The nucleic acids may be natural, synthetic or a combination thereof. The nucleic acids may be RNA, mRNA, DNA or cDNA.
[100] Nucleic acids also include expression vectors, such as plasmids, or viral vectors, or linear vectors, or vectors that integrate into chromosomal DNA. Expression vectors can contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Such sequences are well known for a variety of cells. The origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria. In eukaryotic host cells, e.g., mammalian cells, the expression vector can be integrated into the host cell chromosome and then replicate with the host chromosome. Similarly, vectors can be integrated into the chromosome of prokaryotic cells.
[101] Expression vectors also generally contain a selection gene, also termed a selectable marker. Selectable markers are well-known in the art for prokaryotic and eukaryotic cells, including host cells of the invention. Generally, the selection gene encodes a protein necessary for the survival or growth of transformed host cells grown in a selective culture medium. Host cells not transformed with the vector containing the selection gene will not survive in the culture medium. Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media, e.g., the gene encoding D-alanine racemase for Bacilli. In some embodiments, an exemplary selection scheme utilizes a drug to arrest growth of a host cell. Those cells that are successfully transformed with a heterologous gene produce a protein conferring drug resistance and thus survive the selection
regimen. Other selectable markers for use in bacterial or eukaryotic (including mammalian) systems are well-known in the art.
[102] An example of a promoter that is capable of expressing a transgene encoding an immune binding protein in a mammalian host cell is the EFla promoter. The native EFla promoter drives expression of the alpha subunit of the elongation factor- 1 complex, which is responsible for the enzymatic delivery of aminoacyl tRNAs to the ribosome. The EFla promoter has been extensively used in mammalian expression plasmids and has been shown to be effective in driving expression from transgenes cloned into a lentiviral vector. See, e.g., Milone et al., Mol. Ther. 17(8): 1453-1464 (2009), which is incorporated by reference in its entirety for all purposes. Another example of a promoter is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a strong constitutive promoter sequence capable of driving high levels of expression of any polynucleotide sequence operatively linked thereto. Other constitutive promoter sequences may also be used, including, but not limited to the simian virus 40 (SV40) early promoter, mouse mammary tumor virus promoter (MMTV), human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter, MoMuLV promoter, phosphoglycerate kinase (PGK) promoter, MND promoter (a synthetic promoter that contains the U3 region of a modified MoMuLV LTR with myeloproliferative sarcoma virus enhancer, see, e.g., Li et al., J. Neurosci. Methods vol. 189, pp. 56-64 (2010) which is incorporated by reference in its entirety for all purposes), an avian leukemia virus promoter, an Epstein-Barr virus immediate early promoter, a Rous sarcoma virus promoter, as well as human gene promoters such as, but not limited to, the actin promoter, the myosin promoter, the elongation factor- la promoter, the hemoglobin promoter, and the creatine kinase promoter. Further, the invention is not limited to the use of constitutive promoters.
[103] Inducible promoters are also contemplated herein. Examples of inducible promoters include, but are not limited to a metallothionine promoter, a glucocorticoid promoter, a progesterone promoter, a tetracycline promoter, a c-fos promoter, the T-REx system of ThermoFisher which places expression from the human cytomegalovirus immediate-early promoter under the control of tetracycline operator(s), and RheoSwitch promoters of Intrexon. Karzenowski, D. et al., BioTechiques 39: 191-196 (2005); Dai, X. et al., Protein Expr. Purif 42:236-245 (2005); Palli, S. R. et al., Eur. J. Biochem. 270: 1308-1515 (2003); Dhadialla, T. S. et al., Annual Rev. Entomol. 43:545-569 (1998); Kumar, M. B, et al., J. Biol. Chem. 279:27211- 27218 (2004); Verhaegent, M. et al., Annal. Chem. 74:4378-4385 (2002); Katalam, A. K., et al., Molecular Therapy 13 : S 103 (2006); and Karzenowski, D. et al., Molecular Therapy 13 : S 194
(2006), U.S. Patent Nos. 8,895,306, 8,822,754, 8,748,125, 8,536,354, all of which are incorporated by reference in their entirety for all purposes.
[104] Expression vectors typically have promoter elements, e.g., enhancers, to regulate the frequency of transcriptional initiation. Typically, these are located in the region 30-110 bp upstream of the start site, although a number of promoters have been shown to contain functional elements downstream of the start site as well. The spacing between promoter elements frequently is flexible, so that promoter function is preserved when elements are inverted or moved relative to one another. In the thymidine kinase (tk) promoter, the spacing between promoter elements can be increased to 50 bp apart before activity begins to decline. Depending on the promoter, it appears that individual elements can function either cooperatively or independently to activate transcription.
[105] Control regions suitable for a bacterial host cell can be used in the expression vector. Suitable control regions for directing transcription of the nucleic acid constructs include, for example, the control regions obtained from the E. coli lac operon, Streptomyces coelicolor agarase gene (dagA), Bacillus subtilis levansucrase gene (sacB), Bacillus licheniformis alpha-amylase gene (amyL), Bacillus stearothermophilus maltogenic amylase gene (amyM), Bacillus amyloliquefaciens alpha-amylase gene (amyQ), Bacillus licheniformis penicillinase gene (penP), Bacillus subtilis xylA and xylB genes, and the prokaryotic beta-lactamase gene, the tac promoter, or the T7 promoter.
[106] In some embodiments, control regions for filamentous fungal host cells, include control regions obtained from the genes for Aspergillus oryzae TAKA amylase, Rhizomucor miehei aspartic proteinase, Aspergillus niger neutral alpha-amylase, Aspergillus niger acid stable alphaamylase, Aspergillus niger ox Aspergillus awamori glucoamylase (glaA), Rhizomucor miehei lipase, Aspergillus oryzae alkaline protease, Aspergillus oryzae triose phosphate isomerase, Aspergillus nidulans acetamidase, and Fusarium oxysporum trypsin-like protease (WO 96/00787), as well as the NA2-tpi promoter (a hybrid of the promoters from the genes for Aspergillus niger neutral alpha-amylase and Aspergillus oryzae triose phosphate isomerase), and mutant, truncated, and hybrid control regions thereof. Exemplary yeast cell control regions can be from the genes for Saccharomyces cerevisiae enolase (ENO-1), Saccharomyces cerevisiae galactokinase (GALI), Saccharomyces cerevisiae alcohol dehydrogenase/glyceraldehyde-3- phosphate dehydrogenase (ADH2/GAP), and Saccharomyces cerevisiae 3 -phosphoglycerate kinase.
[107] Exemplary control regions for insect cells include, among others, those based on polyhedron, PCNA, OplE2, OplEl, Drosophila metallothionein, and Drosophila actin 5C. In some embodiments, insect cell promoters can be used with Baculoviral vectors.
[108] Exemplary control regions for plant cells include, among others, those based on cauliflower mosaic virus (CaMV) 35S, polyubiquitin gene (PvUbil and PvUbi2), rice (Oryza saliva) actin 1 (OsActl) and actin 2 (OsAct2) control regions, the maize ubiquitin 1 (ZmUbil) control region, and multiple rice ubiquitin (RUBQ1, RUBQ2, rubi3) control regions.
[109] The expression vector can contain one or more selectable markers, which permit selection of transformed cells. A selectable marker is a gene the product of which provides for biocide or viral resistance, resistance to heavy metals, prototrophy to auxotrophs, and the like. Examples of bacterial selectable markers are the dal genes from Bacillus subtilis or Bacillus Ucheniformis. or markers, which confer antibiotic resistance such as ampicillin, kanamycin, chloramphenicol (Example 1) or tetracycline resistance. Suitable markers for yeast host cells are ADE2, HIS3, LEU2, LYS2, MET3, TRP1, and URA3. Selectable markers for use in a filamentous fungal host cell include, but are not limited to, amdS (acetamidase), argB (ornithine carbamoyltransferase), bar (phosphinothricin acetyltransferase), hph (hygromycin phosphotransferase), niaD (nitrate reductase), pyrG (orotidine-5'-phosphate decarboxylase), sC (sulfate adenyltransferase), and trpC (anthranilate synthase), as well as equivalents thereof. Embodiments for use in an Aspergillus cell include the amdS and pyrG genes of Aspergillus nidulans ox Aspergillus oryzae and the bar gene of Streptomyces hygroscopicus.
[HO] It may be desirable to modify the polypeptides described herein. One of skill will recognize many ways of generating alterations in a given nucleic acid construct to generate variant polypeptides Such well-known methods include site-directed mutagenesis, PCR amplification using degenerate oligonucleotides, exposure of cells containing the nucleic acid to mutagenic agents or radiation, chemical synthesis of a desired oligonucleotide (e.g., in conjunction with ligation and/or cloning to generate large nucleic acids) and other well-known techniques (see, e.g., Gillam and Smith, Gene 8:81-97, 1979; Roberts et al., Nature 328:731-734, 1987, which is incorporated by reference in its entirety for all purposes). The recombinant nucleic acids encoding the polypeptides herein can be modified to provide preferred codons which enhance translation of the nucleic acid in a selected organism.
[Hl] The polynucleotides described herein also include polynucleotides including nucleotide sequences that are substantially equivalent to the polynucleotides described herein. Polynucleotides according to the invention can have at least about 80%, more typically at least about 90%, and even more typically at least about 95%, sequence identity to a polynucleotide of
the invention. The invention also provides the complement of the polynucleotides including a nucleotide sequence that has at least about 80%, more typically at least about 90%, and even more typically at least about 95%, sequence identity to a polynucleotide encoding a polypeptide recited above. The polynucleotide can be DNA (genomic, cDNA, amplified, or synthetic) or RNA. Methods and algorithms for obtaining such polynucleotides are well known to those of skill in the art and can include, for example, methods for determining hybridization conditions which can routinely isolate polynucleotides of the desired sequence identities.
[112] Nucleic acids which encode protein analogs or variants in accordance with those described herein (z.e., wherein one or more amino acids are designed to differ from the wild type polypeptide) may be produced using site directed mutagenesis or PCR amplification in which the primer(s) have the desired point mutations. For a detailed description of suitable mutagenesis techniques, see Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989) and/or Current Protocols in Molecular Biology, Ausubel et al., eds, Green Publishers Inc. and Wiley and Sons, N.Y (1994), each of which is incorporated by reference in its entirety for all purposes. Chemical synthesis using methods well known in the art, such as that described by Engels et al., Angew Chem Inti Ed. 28:716-34, 1989 (which is incorporated by reference in its entirety for all purposes), may also be used to prepare such nucleic acids.
[113] Amino acid “substitutions” for creating variants can be preferably the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, z.e., conservative amino acid replacements. Amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved. For example, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine; polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine; positively charged (basic) amino acids include arginine, lysine, and histidine; and negatively charged (acidic) amino acids include aspartic acid and glutamic acid.
[114] The nucleic acids described herein can be linked to another nucleic acid so as to be expressed under control of a suitable promoter. The nucleic acid can be also linked to, in order to attain efficient transcription of the nucleic acid, other regulatory elements that cooperate with a promoter or a transcription initiation site, for example, a nucleic acid comprising an enhancer sequence, a polyA site, or a terminator sequence. In addition, a gene that can be a marker for confirming expression of the nucleic acid (e.g. a drug resistance gene, a gene encoding a reporter enzyme, or a gene encoding a fluorescent protein) may be incorporated.
[115] When the nucleic acid described herein is introduced into a cell ex vivo, the nucleic acid of may be combined with a substance that promotes transference of a nucleic acid into a cell, for example, a reagent for introducing a nucleic acid such as a liposome or a cationic lipid, in addition to the aforementioned excipients. Alternatively, a vector carrying the nucleic acid can also be useful. Particularly, a composition in a form suitable for administration to a living body which contains the nucleic acid of the present invention carried by a suitable vector is suitable for in vivo gene therapy.
Host Cells
[116] Nucleic acids encoding an immune binding protein described herein (e.g., an antibody) can be cloned into an appropriate expression vector for expression of immune binding protein in a host cell. Host cells include, for example, bacterial, fungi, or mammalian host cells. The host cell can be a bacterium including, for example, Bacillus, such as B. lichenformis or B. subliHs: Pantoea, such as P. cilrea: Pseudomonas, such as P. alcaligenes,' Streptomyces, such as S. lividans or S. rubiginosus,' Escherichia, such as E. coli\ Enter obacter, Streptococcus,' Archaea, such as Methanosarcina mazer, or Corynebacterium, such as C. glutamicum.
[117] The host cells can be fungi cells, including, but not limited to, fungi of the genera Saccharomyces, Klyuveromyces, Candida, Pichia, Debaromyces, Hansenula, Yarrowia, Zygosaccharomyces, or Schizosaccharomyces . In some embodiments, the host cell is a fungi, including, among others, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Kluyveromyces lactis, Kluyveromyces marxianus, Aspergillus terreus, Aspergillus niger, Pichia pastoris, Rhizopus arrhizus, Rhizobus oryzae, Yarrowia lipolytica, and the like. The eukaryotic cells can be algal, including but not limited to algae of the genera Chlorella, Chlamydomonas, Scenedesmus, Isochrysis, Dunaliella, Tetraselmis, Nannochloropsis, or Prototheca. The algae can be a green algae, red algae, glaucophytes, chlorarachniophytes, euglenids, chromista, or dinoflagellates.
[118] The eukaryotic cells can be mammalian cells, such as mouse, rat, rabbit, hamster, porcine, bovine, feline, or canine. The mammalian cells can be cells of primates, including but not limited to, monkeys, chimpanzees, gorillas, and humans. The mammalians cells can be mouse cells, as mice routinely function as a model for other mammals, most particularly for humans (see, e.g, Hanna, J. et al., Science 318: 1920-23, 2007; Holtzman, D.M. et al., J Clin Invest. 103(6):R15-R21, 1999; Warren, R.S. et al., J Clin Invest. 95: 1789-1797, 1995; each publication is incorporated by reference in its entirety for all purposes). Animal cells include, for example, fibroblasts, epithelial cells (e.g., renal, mammary, prostate, lung), keratinocytes, hepatocytes, adipocytes, endothelial cells, and hematopoietic cells. In some embodiments, the animal cells are adult cells (e.g., terminally differentiated, dividing or non-dividing) or embryonic cells (e.g., blastocyst cells, etc.)
or stem cells. The animal cell can be a cell line derived from an animal or other source, such as a Chinese hamster ovary cell line (CHO cell), or murine myeloma cell lines (NS0, Sp2/0), or human cell lines including, for example, HEK293, HT-1080, or PER.C6.
[119] The mammalian cell can be a cell found in the circulatory system of a mammal, including humans. Exemplary circulatory system cells include, among others, red blood cells, platelets, plasma cells, T-cells, natural killer cells, B-cells, macrophages, neutrophils, or the like, and precursor cells of the same. As a group, these cells are defined to be circulating eukaryotic cells of the invention. The mammalian cells can be derived from any of these circulating eukaryotic cells. The immiuner binding proteins described herein may be used with any of these circulating cells or cells derived from the circulating cells. The mammalian cell can be a T-cell or T-cell precursor or progenitor cell. The mammalian cell can be a helper T-cell, a cytotoxic T-cell, a memory T-cell, a regulatory T-cell, a natural killer T-cell, a mucosal associated invariant T-cell, a gamma delta T cell, or a precursor or progenitor cell to the aforementioned. The mammalian cell can be a natural killer cell, or a precursor or progenitor cell to the natural killer cell. The mammalian cell can be a B-cell, or a plasma cell, or a B-cell precursor or progenitor cell. The mammalian cell can be a neutrophil or a neutrophil precursor or progenitor cell. The mammalian cell can be a megakaryocyte or a precursor or progenitor cell to the megakaryocyte. The mammalian cell can be a macrophage or a precursor or progenitor cell to a macrophage.
[120] A source of cells can be obtained from a subject. The subject may be any living organism. Examples of subjects include humans, dogs, cats, mice, rats, and transgenic species thereof. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. Any number of T cell lines available in the art, may be used. T cells can be obtained from a unit of blood collected from a subj ect using any number of techniques known to the skilled artisan, such as Ficoll separation. Cells from the circulating blood of an individual can be obtained by apheresis. The apheresis product typically contains lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and platelets. The cells collected by apheresis may be washed to remove the plasma fraction and to place the cells in an appropriate buffer or media for subsequent processing steps. The cells can be washed with phosphate buffered saline (PBS). In an alternative aspect, the wash solution lacks calcium and may lack magnesium or may lack many if not all divalent cations. Initial activation steps in the absence of calcium can lead to magnified activation.
[121] Plant cells can be cells of monocotyledonous or dicotyledonous plants, including, but not limited to, alfalfa, almonds, asparagus, avocado, banana, barley, bean, blackberry, brassicas,
broccoli, cabbage, canola, carrot, cauliflower, celery, cherry, chicory, citrus, coffee, cotton, cucumber, eucalyptus, hemp, lettuce, lentil, maize, mango, melon, oat, papaya, pea, peanut, pineapple, plum, potato (including sweet potatoes), pumpkin, radish, rapeseed, raspberry, rice, rye, sorghum, soybean, spinach, strawberry, sugar beet, sugarcane, sunflower, tobacco, tomato, turnip, wheat, zucchini, and other fruiting vegetables (e.g. tomatoes, pepper, chili, eggplant, cucumber, squash etc.), other bulb vegetables (e.g., garlic, onion, leek etc.), other pome fruit (e.g. apples, pears etc.), other stone fruit (e.g., peach, nectarine, apricot, pears, plums etc.), Arabidopsis, woody plants such as coniferous and deciduous trees, an ornamental plant, a perennial grass, a forage crop, flowers, other vegetables, other fruits, other agricultural crops, herbs, grass, or perennial plant parts (e.g., bulbs; tubers; roots; crowns; stems; stolons; tillers; shoots; cuttings, including un-rooted cuttings, rooted cuttings, and callus cuttings or callus-generated plantlets; apical meristems etc.). The term “plants” refers to all physical parts of a plant, including seeds, seedlings, saplings, roots, tubers, stems, stalks, foliage and fruits.
CDR Grafted Antibodies
[122] CDR grafted forms of antibodies are chimeric immunoglobins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')2 or other antigen-binding subsequences of antibodies) which contain CDR sequences derived from one immunoglobulin grafted into the framework sequences of a second immunoglobulin. CDR grafted antibodies include immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient antibody are replaced by residues from a CDR of another antibody (donor antibody) having the desired specificity, affinity and capacity. In some instances, Fv framework residues of the recipient antibody are replaced by corresponding residues from the donor antibody. CDR grafted antibodies may also comprise residues which are found neither in the recipient antibody nor in the donor CDR or framework sequences. In general, the CDR grafted antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a donor antibody and all or substantially all of the FR regions are those of a recipient antibody consensus sequence. The CDR grafted antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a recipient antibody [Jones et al., Nature, 321 :522-525 (1986); Riechmann et al., Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992), all of which are incorporated by reference in their entirety for all purposes],
[123] Humanization is one type of CDR grafting to make a chimeric antibody. Methods for humanizing non-human antibodies are well known in the art. Generally, humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-
human amino acid residues are often referred to as "import" residues, which are typically taken from an "import" variable domain. Humanization can be essentially performed following the method of Winter and co-workers [Jones et al., Nature, 321 :522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239: 1534-1536 (1988), all of which are incorporated by reference in their entirety for all purposes], by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such "humanized" antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567 which is incorporated by reference in its entirety for all purposes), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequences from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
Multispecific Antibodies
[124] It may be desirable to generate multispecific (e.g. bispecific) antibodies having binding specificities for at least two different epitopes. Exemplary bispecific antibodies may bind to two different epitopes of SARS-CoV-2. Alternatively, an anti-SARS-CoV-2 arm may be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g., CD2 or CD3), or Fc receptors for IgG (Fc gamma Receptor), such as FcgRI (CD64), FcgRII (CD32) and FcgRIII (CD 16). Bispecific antibodies may also be used to localize cytotoxic agents. These antibodies possess an SARS-CoV-2-binding arm and an arm which binds the cytotoxic agent (e.g., saporin, anti-interferon-alpha, vinca alkaloid, ricin A chain, methotrexate or radioactive isotope hapten). Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g., F(ab')2 bispecific antibodies).
[125] According to another approach for making bispecific antibodies, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH3 domain of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g., tyrosine or tryptophan). Compensatory "cavities" of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g., alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers. See WO96/27011 published Sep. 6, 1996, which is incorporated by reference in its entirety for all purposes.
[126] Bispecific antibodies include cross-linked or "heteroconjugate" antibodies. For example, one of the antibodies in the heteroconjugate can be coupled to avidin, the other to biotin. Heteroconjugate antibodies may be made using any convenient cross-linking methods. Suitable cross-linking agents are well known in the art, and are disclosed in U.S. Pat. No. 4,676,980, which is incorporated by reference in its entirety for all purposes, along with a number of cross-linking techniques.
[127] Techniques for generating bispecific antibodies from antibody fragments have also been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science 229:81 (1985) (which is incorporated by reference in its entirety for all purposes) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab')2 fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab' fragments generated are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab'-TNB derivatives is then reconverted to the Fab'-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab'-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes. In yet a further embodiment, Fab'-SH fragments directly recovered from E. coli can be chemically coupled in vitro to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175:217 225 (1992) (which is incorporated by reference in its entirety for all purposes).
[128] Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J. Immunol. 148(5): 1547 1553 (1992), which is incorporated by reference in its entirety for all purposes. The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab' portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers. The "diabody" technology described by Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444 6448 (1993) which is incorporated by reference in its entirety for all purpose, has provided an alternative mechanism for making bispecific antibody fragments. The fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making
bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See Gruber et al., J. Immunol. 152:5368(1994) which is incorporated by reference in its entirety for all purposes. Alternatively, the bispecific antibody may be a "linear antibody" produced as described in Zapata et al. Protein Eng. 8(10): 1057 1062 (1995) which is incorporated by reference in its entirety for all purposes.
[129] Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991) which is incorporated by reference in its entirety for all purposes.
Modified Antibodies
[130] An anti-SARS-CoV-2 antibody can include a moiety that extends a half-life (T1/2) or/and the duration of action of the antibody. The moiety can extend the circulation T 1/2, blood T 1/2, plasma T1/2, serum T1/2, terminal T1/2, biological T1/2, elimination T1/2 or functional T1/2, or any combination thereof, of the antibody.
[131] An anti-SARS-CoV-2 antibody may be modified by a single moiety. Alternatively, an anti- SARS-CoV-2 antibody may be modified by two or more substantially similar or identical moieties or two or more moieties of the same type. An anti-SARS-CoV-2 antibody may include two or more moieties of different types, or two or more different types of moieties. Two or more anti-SARS- CoV-2 antibodies can also be attached to one moiety. The attachment between the anti-SARS- CoV-2 antibody and the moiety can be covalent or noncovalent.
[132] A polypeptide moiety can be recombinantly fused to the N-terminus or the C-terminus of the heavy chain or the light chain of an anti-SARS-CoV-2 antibody, optionally via a linker. The linker may contain about 4-30 amino acid residues. The linker may contain from about 6 or 8 amino acid residues to about 20 amino acid residues, or from about 6 or 8 amino acid residues to about 15 amino acid residues.
[133] A protracting moiety can be human serum albumin (HSA) or a portion thereof (e.g., domain III) that binds to the neonatal Fc receptor (FcRn). The HSA or FcRn-binding portion thereof can optionally have one or more mutations that confer a beneficial property or effect. In some embodiments, the HSA or FcRn-binding portion thereof has one or more mutations that enhance pH-dependent HSA binding to FcRn or/and increase HSA half-life, such as K573P or/and E505G/V547A. A protracting moiety can be an unstructured polypeptide.
[134] A protracting moiety can be a carboxy-terminal peptide (CTP) derived from the P-subunit of human chorionic gonadotropin (hCG). In the human body, the fourth, fifth, seventh and eight serine residues of the 34-aa CTP of hCG-P typically are attached to O-glycans terminating with a sialic acid residue.
[135] A protracting moiety can be 1, 2, 3, 4, 5 or more moi eties of a synthetic polymer. The synthetic polymer can be biodegradable or non-biodegradable. Biodegradable polymers useful as protracting moieties include, but are not limited to, poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) and poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA). Non-biodegradable polymers useful as protracting moieties include without limitation polyethylene glycol) (PEG), polyglycerol, poly(A-(2-hydroxypropyl)methacrylamide) (PHPMA), polyoxazolines and poly(A-vinylpyrrolidone) (PVP). A synthetic polymer can be polyethylene glycol (PEG). PEGylation can be done by chemical or enzymatic, site-specific coupling or by random coupling.
[136] The protracting moieties can also 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, proly propylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. 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 a therapy under defined conditions, etc.
[137] The individual mass (e.g., average molecular weight), or the total mass, of the one or more synthetic polymer moieties can be about 10-50, 10-20, 20-30, 30-40 or 40-50 kDa, or about 10, 20, 30, 40 or 50 kDa. The individual mass (e.g., average MW), or the total mass, of the one or more synthetic polymer moieties also can be greater than about 50 kDa, such as about 50-100, 50-60, 60- 70, 70-80, 80-90 or 90-100 kDa, or about 60, 70, 80, 90 or 100 kDa. Moreover, the mass (e.g., average MW) of an individual synthetic polymer moiety can be less than about 10 kDa, such as about 1-5 or 5-10 kDa, or about 5 kDa. The individual mass (e.g., average MW), or the total mass, of the one or more synthetic polymer (e.g., PEG) moieties can be about 20 or 40 kDa.
Pharmaceutical Compositions
[138] Antibodies specifically binding SARS-CoV-2 identified herein, as well as other immune binding proteins identified by the screening assays disclosed hereinbefore, can be administered for the treatment of various disorders in the form of pharmaceutical compositions.
[139] Pharmaceutical compositions generally are prepared according to current good manufacturing practice (GMP), as recommended or required by, e.g., the Federal Food, Drug, and Cosmetic Act §501(a)(2)(B) and the International Conference on Harmonisation Q7 Guideline.
[140] Pharmaceutical compositions/formulations can be prepared in sterile form. For example, pharmaceutical compositions/formulations for parenteral administration by injection or infusion generally are sterile. Sterile pharmaceutical compositions/formulations are compounded or manufactured according to pharmaceutical-grade sterilization standards known to those of skill in the art, such as those disclosed in or required by the United States Pharmacopeia Chapters 797, 1072 and 1211, and 21 Code of Federal Regulations 211.
[141] Pharmaceutically acceptable excipients and carriers include pharmaceutically acceptable substances, materials and vehicles. Non-limiting examples of types of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersing agents, disintegration agents, emulsifying agents, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pH adjusters, absorption-delaying agents, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweetening agents, flavoring agents, coloring agents, encapsulating materials and coating materials. The use of such excipients in pharmaceutical formulations is known in the art. For example, conventional vehicles and carriers include without limitation oils (e.g., vegetable oils such as olive oil and sesame oil), aqueous solvents {e.g., saline, buffered saline (e.g., phosphate-buffered saline [PBS]) and isotonic solutions (e.g., Ringer’s solution)}, and organic solvents (e.g., dimethyl sulfoxide [DMSO] and alcohols [e.g., ethanol, glycerol and propylene glycol]). Except insofar as any conventional excipient or carrier is incompatible with an anti-SARS-CoV2 antibody or a fragment thereof, the disclosure encompasses the use of conventional excipients and carriers in formulations containing an anti-SARS-CoV2 antibody or a fragment thereof. See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania) (2005); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Co. (2007); and Pharmaceutical Pre-formulation and Formulation, Gibson, Ed., CRC Press (Boca Raton, Florida) (2004).
[142] Appropriate formulation can depend on various factors, such as the route of administration chosen. Potential routes of administration of a pharmaceutical composition comprising an anti- SARS-CoV2 antibody or a fragment thereof include without limitation oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intraperitoneal, intramedullary, intrathecal and topical), intracavitary, and topical (including dermal/epicutaneous, transdermal, mucosal, transmucosal, intranasal [e.g., by nasal spray or drop], intraocular [e.g., by eye drop], pulmonary [e.g., by oral or nasal inhalation], buccal, sublingual, rectal [e.g., by suppository], and vaginal [e.g., by suppository]). Topical formulations can be designed to produce a local or systemic therapeutic effect. In certain embodiments, an anti-SARS-CoV2 antibody or a fragment thereof is administered parenterally (e.g., intravenously, subcutaneously, intramuscularly or intraperitoneally) by injection (e.g., as a bolus) or by infusion over a period of time.
[143] Excipients and carriers that can be used to prepare parenteral formulations include without limitation solvents (e.g., aqueous solvents such as water, saline, physiological saline, buffered saline [e.g., phosphate-buffered saline], balanced salt solutions [e.g., Ringer’s BSS] and aqueous dextrose solutions), isotonic/iso-osmotic agents (e.g., salts [e.g., NaCl, KC1 and CaC12] and sugars [e.g., sucrose]), buffering agents and pH adjusters (e.g., sodium dihydrogen phosphate [monobasic sodium phosphate]/di sodium hydrogen phosphate [dibasic sodium phosphate], citric acid/sodium citrate and L-histidine/L-histidine HC1), and emulsifiers (e.g., non-ionic surfactants such as polysorbates [e.g., polysorbate 20 and 80] and pol oxamers [e.g., pol oxamer 188]). Protein formulations and delivery systems are discussed in, e.g., A. J. Banga, Therapeutic Peptides and Proteins: Formulation, Processing, and Delivery Systems, 3rd Ed., CRC Press (Boca Raton, Florida) (2015).
[144] The excipients can optionally include one or more substances that increase protein stability, increase protein solubility, inhibit protein aggregation or reduce solution viscosity, or any combination or all thereof. Examples of such substances include without limitation hydrophilic amino acids (e.g., arginine and histidine), polyols (e.g., myo-inositol, mannitol and sorbitol), saccharides {e.g., glucose (including D-glucose [dextrose]), lactose, sucrose and trehalose}, osmolytes (e.g., trehalose, taurine, amino acids [e.g., glycine, sarcosine, alanine, proline, serine, L- alanine and y-aminobutyric acid], and betaines [e.g., trimethylglycine and trimethylamine N- oxide]), and non-ionic surfactants {e.g., alkyl polyglycosides, ProTek® alkylsaccarides (e.g., a monosaccharide [e.g., glucose] or a disaccharide [e.g., maltose or sucrose] coupled to a long-chain fatty acid or a corresponding long-chain alcohol), and polypropylene glycol/polyethylene glycol block co-polymers (e.g., poloxamers [e.g., PluronicTM F-68], and Genapol® PF-10 and variants thereof)}. Because such substances increase protein solubility, they can be used to increase protein
concentration in a formulation. Higher protein concentration in a formulation is particularly advantageous for subcutaneous administration, which has a limited volume of bolus administration (e.g., < about 1.5 mL). In addition, such substances can be used to stabilize proteins during the preparation, storage and reconstitution of lyophilized proteins. Formulations and excipients for inhalation delivery are known in the art including, for example, those described in US Patent No. 5,898,028 which is hereby incorporated by reference in its entirety for all purposes.
[145] For parenteral (e.g., intravenous, subcutaneous or intramuscular) administration, a sterile solution or suspension of an anti-SARS-CoV2 antibody in an aqueous solvent containing one or more excipients can be prepared beforehand and can be provided in, e.g., a pre-filled syringe. Alternatively, an anti-SARS-CoV2 antibody can be dissolved or suspended in an aqueous solvent that can optionally contain one or more excipients prior to lyophilization (freeze-drying). Shortly prior to parenteral administration, the lyophilized anti-SARS-CoV2 antibody stored in a suitable container (e.g., a vial) can be reconstituted with, e.g., sterile water that can optionally contain one or more excipients. If the anti-SARS-CoV2 antibody is to be administered by infusion (e.g., intravenously), the solution or suspension of the reconstituted anti-SARS-CoV2 antibody can be added to and diluted in an infusion bag containing, e.g., sterile saline (e.g., about 0.9% NaCl).
[146] Excipients that enhance transmucosal penetration of smaller proteins include without limitation cyclodextrins, alky saccharides (e.g., alkyl glycosides and alkyl maltosides [e.g., tetradecylmaltoside]), and bile acids (e.g., cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, glycodeoxycholic acid, chenodeoxycholic acid and dehydrocholic acid).
[147] Excipients that enhance transepithelial or transdermal penetration of smaller proteins include without limitation chemical penetration enhancers (CPEs, including fatty acids [e.g., oleic acid]), cell-penetrating peptides {CPPs, including arginine-rich CPPs [e.g., polyarginines such as R6-R11 (e.g., R6 and R9) and TAT -related CPPs such as TAT(49-57)] and amphipathic CPPs [e.g., Pep-1 and penetratin]}, and skin-penetrating peptides (SPPs, such as the skin-penetrating and cellentering [SPACE] peptide). Transdermal penetration of smaller proteins can be further enhanced by use of a physical enhancement technique, such as iontophoresis, cavitational or non-cavitational ultrasound, electroporation, thermal ablation, radio frequency, microdermabrasion, microneedles or jet injection. US 2007/0269379 provides an extensive list of CPEs. F. Milletti, Drug Discov. Today, 17:850-860 (2012) is a review of CPPs. R. Ruan et al., Ther. Deliv., 7:89-100 (2016) discuss CPPs and SPPs for transdermal delivery of macromolecules, and M. Prausnitz and R. Langer, Nat. Biotechnol., 26: 1261-1268 (2008) discuss a variety of transdermal drug-delivery methods.
[148] An anti-SARS-CoV-2 antibody can be delivered from a sustained-release composition. As used herein, the term “sustained-release composition” encompasses sustained-release, prolonged-
release, extended-release, slow-release and controlled-release compositions, systems and devices. Protein delivery systems are discussed in, e.g., Banga (supra). A sustained-release composition can deliver a therapeutically effective amount of an anti-SARS-CoV2 antibody over a prolonged time period. In some embodiments, a sustained-release composition delivers an anti-SARS-CoV2 antibody over a period of at least about 3 days, 1 week, 2 weeks, 3 weeks, 1 month (4 weeks), 6 weeks, 2 months, 3 months or longer. A sustained-release composition can be administered, e.g., parenterally (e.g., intravenously, subcutaneously or intramuscularly).
[149] A sustained-release composition of a protein can be in the form of, e.g., a particulate system, a lipid or oily composition, or an implant. Particulate systems include without limitation nanoparticles, nanospheres, nanocapsules, microparticles, microspheres and microcapsules. Nanoparticulate systems generally have a diameter or an equivalent dimension smaller than about 1 pm. In certain embodiments, a nanoparticle, nanosphere or nanocapsule has a diameter or an equivalent dimension of no more than about 500, 400 or 300 nm, or no more than about 200, 150 or 100 nm. In some embodiments, a microparticle, microsphere or microcapsule has a diameter or an equivalent dimension of about 1-200, 100-200 or 50-150 pm, or about 1-100, 1-50 or 50-100 pm. A nano- or microcapsule typically contains the therapeutic agent in the central core, while the therapeutic agent typically is dispersed throughout a nano- or microparticle or sphere. In certain embodiments, a nanoparticulate system is administered intravenously, while a microparticulate system is administered subcutaneously or intramuscularly.
[150] In some embodiments, a sustained-release particulate system or implant is made of a biodegradable polymer or/and a hydrogel. In certain embodiments, the biodegradable polymer comprises lactic acid or/and glycolic acid [e.g., an L-lactic acid-based copolymer, such as poly(L- lactide-co-glycolide) or poly(L-lactic acid-co-D,L-2-hydroxyoctanoic acid)]. Non-limiting examples of polymers of which a hydrogel can be composed include polyvinyl alcohol, acrylate polymers (e.g., sodium polyacrylate), and other homopolymers and copolymers having a relatively large number of hydrophilic groups (e.g., hydroxyl or/and carboxylate groups). The biodegradable polymer of the particulate system or implant can be selected so that the polymer substantially completely degrades around the time the period of treatment is expected to end, and so that the byproducts of the polymer’s degradation, like the polymer, are biocompatible.
[151] Alternatively, a sustained-release composition of a protein can be composed of a non- biodegradable polymer. Examples of non-biodegradable polymers include without limitation poloxamers (e.g., poloxamer 407). Sustained-release compositions of a protein can be composed of other natural or synthetic substances or materials, such as hydroxyapatite.
[152] Sustained-release lipid or oily compositions of a protein can be in the form of, e.g., liposomes, micelles (e.g., those composed of biodegradable natural or/and synthetic polymers, such as lactosomes), and emulsions in an oil.
[153] A sustained-release composition can be formulated or designed as a depot, which can be injected or implanted, e.g., subcutaneously or intramuscularly. A depot can be in the form of, e.g., a polymeric particulate system, a polymeric implant, or a lipid or oily composition. A depot formulation can comprise a mixture of a protein and, e.g., a biodegradable polymer [e.g., poly(lactide-co-glycolide)] or a semi-biodegradable polymer (e.g., a block copolymer of lactic acid and PEG) in a biocompatible solvent system, whether or not such a mixture forms a particulate system or implant.
[154] A pharmaceutical composition can be presented in unit dosage form as a single dose wherein all active and inactive ingredients are combined in a suitable system, and components do not need to be mixed to form the composition to be administered. The unit dosage form generally contains an effective dose of the therapeutic agent. A representative example of a unit dosage form is a single-use pen comprising a pre-filled syringe, a needle and a needle cover for parenteral (e.g., intravenous, subcutaneous or intramuscular) injection of the therapeutic agent.
[155] Alternatively, a pharmaceutical composition can be presented as a kit in which the therapeutic agent, excipients and carriers (e.g., solvents) are provided in two or more separate containers (e.g., ampules, vials, tubes, bottles or syringes) and need to be combined to form the composition to be administered. The kit can contain instructions for storing, preparing and administering the composition (e.g., a solution to be injected intravenously or subcutaneously).
Methods for Making Immune Binding Proteins
[156] Suitable host cells for making immune binding proteins recombinantly (e.g., anti-SARS- CoV-2 antibodies) include higher eukaryote cells described herein, including vertebrate host cells. Propagation of vertebrate cells in culture (tissue culture) has become a routine procedure. Examples of useful mammalian host cell lines are monkey kidney CV 1 line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture. Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BEK, ATCC CCL 10); Chinese hamster ovary cells/-DHFR (CHO, Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); mouse sertoli cells (TM4, Mather. Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat liver cells (BRL 3 A, ATCC CRL 1442); human lung cells (W138. ATCC CCL 75): human liver cells (Hep G2, HB 8065); mouse mammary tumor (MMT 060562.
ATCC CCL51); TRI cells (Mather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982)); MRC 5 cells; FS4 cells: and a human hepatoma line (Hep G2).
[157] The host cells used to produce the immune binding proteins described herein (e.g., anti- SARS-CoV-2 antibodies) may be cultured in a variety of media. Commercially available media such as Ham's F10 (Sigma), Minimal Essential Medium ((MEM), (Sigma), RPMI-1640 (Sigma), and Dulbecco's Modified Eagle's Medium ((DMEM). Sigma) are suitable for culturing the host cells. In addition, any of the media described in Ham et al., Meth. Enz. 58:44 (1979), Barnes et al., Anal. Biochem. 102:255 (1980), U.S. Pat. Nos. 4,767,704; 4,657,866; 4,927,762; 4,560,655; or 5,122,469; WO 90/03430; WO 87/00195; or U.S. Pat. No. Re. 30,985 may be used as culture media for the host cells. Any of these media may be supplemented as necessary with hormones and/or other growth factors (such as insulin, transferrin, or epidermal growth factor), salts (such as sodium chloride, calcium, magnesium, and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics (such as GENTAMYCIN™ drug), trace elements (defined as inorganic compounds usually present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Any other necessary supplements may also be included at appropriate concentrations that would be known to those skilled in the art. The culture conditions, such as temperature, pH, and the like, are those previously used with the host cell selected for expression, and will be apparent to the ordinarily skilled artisan.
[158] Anti-SARS-CoV-2 antibodies made recombinantly as described above, will typically have altered glycosylation from naturally occurring human antibodies. For example, if the anti-SARS- CoV-2 antibodies are made in CHO cells, the glycosylation on the full-length antibodies will be non-human, and can change biochemical properties of the antibodies and change the half-life of the antibodies.
[159] The nucleic acids encoding the anti-SARS-CoV-2 antibodies and used to recombinantly produce the anti-SARS-CoV-2 antibodies can be codon optimized for the host cell used to recombinantly make the antibodies. The codon optimization can be done on at least one or more codons of the nucleic acid to make a non-naturally occurring nucleic acid. Methods for codon optimizing nucleic acids for recombinant production are well known in the art.
Combination Therapies
[160] As noted above, the methods herein, include administering to the subject one or more additional therapeutic agents in combination with an antibody or other immune binding proteins obtained (e.g., anti-SARS-CoV-2 antibody). As used herein, the expression “in combination with” means that the additional therapeutic agents is/are administered before, after, or concurrent with the pharmaceutical composition comprising the immune binding proteins described herein (e.g., anti-
SARS-CoV-2 antibody). The term “in combination with” also includes sequential or concomitant administration of the immune binding protein described herein and a second therapeutic agent (which could be a different immune binding protein described herein).
[161] Combination therapies may include an anti-SARS-CoV antibody and any additional therapeutic agent that may be advantageously combined with an antibody described herein, or with a biologically active fragment of an antibody described herein. For example, a second or third therapeutic agent may be employed to aid in reducing the viral load in the lungs, such as an antiviral, for example, Remdesivir (Veklury), ribavirin, nucleoside analogs, etc. The antibodies may also be used in conjunction with other therapies, including a toxoid, a vaccine specific for SARS-CoV-2, a second antibody specific for SARS-CoV-2, or an antibody specific for another SARS-CoV-2 antigen. The additional therapeutic agent can also be one that ameliorates certain symptoms of SARS-CoV-2, such as, for example, cytokine storm, fever, inflammation, etc. Additional therapeutic agents can include, for example, dexamethasone, other corticosteroids, etc.
Applications
[162] The immune binding proteins described herein can be used in therapies for infectious diseases, cancer, allergies, and autoimmune diseases. The methods described herein can be used to make repertoires of immune binding proteins from subjects that have been challenged/infected with an infectious agent. The immune binding proteins described herein can be used in therapies to treat subjects infected with an infectious agent such as coronavirus (e.g., SARS-CoV-2). Addition of the exogenous immune binding protein (e.g., anti -SARS-CoV-2 antibody) helps the subject’s body accelerate its own immune response to a pathogen, in effect “transplanting” the immunity from one individual to another. The immune binding proteins described herein can be used prophylactically to provide protection to those individuals who are particularly susceptible to a disease or particularly susceptible to bad outcomes from a disease. The immune binding proteins described herein can also be used in diagnostic applications. The immune binding proteins described herein can provide information on a subject’s response to a therapy. The immune binding proteins described herein can provide information on a subject’s response to an antibody therapy, small molecule drug therapy, biologic therapy, or cellular immunotherapy.
[163] The immune binding proteins (e.g., anti-SARS-CoV-2antibodies) can be obtained from a subject that neutralized an infectious agent and overcame the infection. The infectious agent can be a bacterial strain of Staphylococci, Streptococcus, Escherichia coli, Pseudomonas, or Salmonella. The infectious agent canbe a Staphylococcus aureus, Neisseria gonorrhoeae, Streptococcus pyogenes, Group A Streptococcus, Group B Streptococcus (Streptococcus agalactiae), Streptococcus pneumoniae, and Clostridium tetani. The infectious agent can be a
bacterial pathogen that may infect host cells including, for example, Helicobacter pyloris, Legionella pneumophiHa. a bacterial strain of Mycobacteria sps. (e.g. M. tuberculosis, M. avium, M. intr acellular e, M. kansaii, or M. gordonea). Neisseria meningitides, Listeria monocytogenes, R. rickettsia, Salmonella spp., Brucella spp., Shigella spp., or certain E. coli strains or other bacteria that have acquired genes with invasive factors. The infectious agent can be a bacterial pathogen that is antibiotic resistant.
[164] The infectious agent can be a viral pathogen including, for example, coronavirus (e.g., SARS-CoV-2), Ebola, Zika, RSV, Retroviridae (e.g. human immunodeficiency viruses such as HIV-1 and HIV-LP), Picornaviridae (e.g. poliovirus, hepatitis A virus, enterovirus, human coxsackievirus, rhinovirus, and echovirus), rubella virus, coronavirus, vesicular stomatitis virus, rabies virus, ebola virus, parainfluenza virus, mumps virus, measles virus, respiratory syncytial virus, influenza virus, hepatitis B virus, parvovirus, Adenoviridae, Herpesviridae [e.g. type 1 and type 2 herpes simplex virus (HSV), varicella-zoster virus, cytomegalovirus (CMV), and herpes virus], Poxviridae (e.g. smallpox virus, vaccinia virus, and pox virus), or hepatitis C virus.
[165] The immune binding proteins described herein can be used to boost the immunity of a subject against an infectious disease (e.g., SARS-CoV-2). For example, in coronavirus infections the body responds within 7-10 days to a challenge; however, in immunocompromised patients such as the elderly or subjects with other underlying risk factors, the immune response timing or extent may be insufficient to fight off the infection, resulting in severe complications and possibly death. By boosting the immune system with antibodies designed to neutralize the relevant strain of coronavirus, the infection in the subject can treated. The immune binding proteins described herein (e.g., anti-SARS-CoV-2 antinbodies) are used to treat infected patients and/or passively immunize vulnerable populations facing an outbreak. The immune binding proteins described herein can be administered prophylactically to protect subjects from infection (e.g., by SARS-CoV-2). Such prophylactic administration of the immune binding proteins can protect at risk groups of subjects from a disease.
[166] The infectious agent can be a coronavirus (e.g., SARS-CoV-2), a herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), varicella zoster, Epstein-Barr, cytomegalovirus (CMV), or Kaposi’s sarcoma viruses. HSV-1 primarily causes oral herpes, ocular herpes, and herpes encephalitis, and occasionally causes genital herpes; HSV-2 primarily causes genital herpes but can also cause oral herpes; varicella zoster causes chickenpox and shingles; Epstein-Barr causes mononucleosis and is associated with several cancers including Burkitt’s lymphoma; CMV causes mononucleosis-like syndrome and congenital/neonatal morbidity and mortality. Some of the herpesviridae, and in particular HSV-1, have been associated with and proposed as causative agents
for Alzheimer’s Disease. In some embodiments, immune binding proteins of the invention can be used to treat and/or passively immunize against these herpesviridae. An injection or topical application of an antibody against HSV-1 or HSV-2 can be employed to reduce the incidence or severity of the effects of herpes outbreaks.
[167] The immune binding proteins described herein can be useful for treating subjects with autoimmune diseases or whom have cytokine storm response to pathogen infections (e.g., SARS- CoV-2). The autoimmune disease can be rheumatoid arthritis, lupus, celiac disease, Sjorgren’s syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, Type 1 diabetes, and the like. The immune binding proteins described herein bind the antigen target of the autoimmune disease or the SARS-CoV-2 without triggering the autoimmune/cytokine storm reaction. For example, the immune binding protein could be an antibody without an Fc region, or could be an antibody in a format that does not interact with the effector cells that are associated with the autoimmune disease. The immune binding protein described herein binds to the autoimmune antigen without triggering an autoimmune reaction and this binding can prevent the subject’s immune system from reacting with the autoimmune antigen reducing the autoimmune disease (this can be a competitive inhibition reaction).
[168] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
EXAMPLES
Example 1 Antibodies Against Coronavirus (SARS-CoV-2)
[169] The work flow of FIG. 3 was adapted for making antibodies against coronavirus SARS- CoV-2. See, for example, USSN 16/826,189 filed March 21, 2020, which is hereby incorporated by reference in its entirety for all purposes. In this work flow, blood/serum samples are obtained from patients who have mounted an immune response to SARS-CoV-2 virus (from contracting SARS-CoV-2 by exposure to other infected patients). A solution of Pierce 1 micron beads bound to SARS-CoV-2 S1+S2 were added to the substrate, 3um BangsLabs COMPEL blue fluorescent beads loaded with a predetermined SARS-CoV-2 antigen (in some assays SARS-CoV-2 SI protein, in others SARS-CoV-2 E+M+S1+S2 protein), 3 um BangsLabs COMPEL green magnetic beads loaded with a separate predetermined SARS-CoV-2 antigen (in some assays SARS-CoV-2 RBD, in others SARS-CoV-2 S2 protein), 6um COMPEL blue magnetic beads loaded with a separate predetermined SARS-CoV-2 protein (in some assays SARS-CoV-2 Receptor Binding Domain). The blood/serum was depleted of T-cells and these T-cell depleted PBMC’s were loaded onto a
substrate. In some cases, PBMC’s from blood were cultured to differentiate them into plasma cells before loading onto substrate. The cells and beads and secondary antibody were incubated for 24 hours under appropriate culture conditions, with a goat anti-human Fab antibody bound to R- phycoerythrin (“secondary antibody”). The microscope was used to identify halos of fluorescent beads that captured secreted antibodies from proximal cells due to antibody/antigen interactions and were stained with the secondary antibody. In this manner it was possible to automatically demultiplex antigen binding based on the secondary antibody fluorescent image pixels masked by positive pixels from the green or blue channels, and optionally masked by pixels positive using a Top Hat transform to further demultiplex antigen specificity by size. Cells with halos were selected with the device and placed into 96 well plates where subsequent molecular biology results in amplification and sequencing of immune receptor nucleic acids.
[170] After picking single cells into lysis buffer, cells were lysed at 70C in the presence of poly dT primer. RT buffer and reverse transcriptase were added and single cell cDNA produced at 55C. Gene specific amplification of heavy and light chains was performed after the addition of DNA polymerase (Kapa HiFi), buffer and primers and PCR thermal cycling. Amplified genes were barcoded with well specific barcodes in a subsequent PCR reaction, all cDNA’s for a single chain from a plate pooled, chain/plate libraries barcoded with chain/plate specific barcodes in a subsequent PCR reaction, and then chain/plate libraries normalized and pooled before loading on an Illumina MiSeq sequencer. Reads were separated by their plate/well/chain and put through an analysis pipeline that involved clustering reads based on sequence entropy to make a consensus assembly, consensus sequences found by aligning all reads in a well/chain/plate barcode group to each assembly and making basecalls by consensus, and then annotating each sequence by alignment with IgBlast against a human germline reference database. Paired antibody genes were then synthesized, cloned into an expression vector and expressed in HEK293 cells and/or as ScFv fragments. Full length antibodies were assayed for binding with ForteBio and Luminex assays.
[171] Results of antigen binding for antibodies 1-402 are show in Table 2.
Example 2 Binding Affinity of Anti-SARS-CoV-2 Antibodies
[172] Affinity of selected anti-SARS-CoV-2 antibodies was measured using mean fluorescence intensity. SARS-CoV-2 antigens were conjugated to Luminex beads and binding assays were performed on a Luminex200 instrument based on the manufacturer's protocol. The following antigens were tested for binding affinity: SI (Sino Biological), S2 (Sino Biological), SI + S2 (Sino Biological), RBD (Sino Biological), NAC SI (The Native Antigen Company), NAC Mosaic (The Native Antigen Company).
[173] Antibodies were attached to a ForteBio AHC antibody probe according to manufacturer’s recommended protocol, equilibrated and then measured against antigens. Signals from a reference sensor were subtracted from the binding measurement and a curve for a 2: 1 kinetic model was fit to the data.
[175] The anti-SARS-CoV-2 antibodies 219, 220 and 226 each bound to the SARS-CoV-2 RBP (receptor binding domain) with affinities of less than 1 picomolar.
Example 3, Development of masked anti-SARS-CoV-2 proteins for diagnostic assays and vaccines
[176] Antibodies discovered in the sequence listing are used to bind their respective proteins at their respective epitopes. Once these antibodies have bound their particular epitopes, a thiol and/or amine reactive PEGylation reagent at ImM is introduced to chemically react with amino acid side chains that are not masked by the antibody binding its epitope. The mixture is added to a Tris and/or DTT buffer to quench the PEGylation reagent and buffer exchanged. The antibody-antigen interaction is broken with heat and/or changes in pH and filtered over a Protein A/G column to remove the blocking antibodies. The resulting protein is PEGylated at all regions except the antibody binding epitope. The protein is used for vaccination in order to elicit an immune response to the original binding epitope and/or diagnostic purposes which seek to identify antibodies that bind the same epitope as the original masking antibody.
Example 4, Development of an antibody-adjuvant vaccine
[177] Antibodies discovered in the sequence listing can be used to bind their respective proteins at their respective epitopes. The antibody/antigen mixture is used as a vaccine to elicit antibody responses at the sites unbound by the antibodies and/or improve TCR responses to the bound antigen through macrophage/dendritic cell engulfment of the antibody-antigen complex and crosspresentation of antigen peptides.
Example 5: Neutralization of SARS-CoV-2 by Anti-SARS-CoV-2 Antibodies
[178] Anti-SARS-CoV-2 antibodies were tested for neutralization activity in an in vitro assay. See, E.g., Crawford et al, Protocol and reagents for pseudotyping lentiviral particles with SARS- CoV2 Spike protein for neutralization assays, 2020, Viruses doi: 19.3390/vl2050513, which is hereby incorporated by reference in its entirety for all purposes. Lentivirus was engineered to express the SARS-CoV-2 spike (1+2) protein, and antibodies were tested for inhibition of infection in HEK293 cells. In this assay the pseudo typed lentivirus infect the HEK293 cells using the spike protein binding to ACE2 on the HEK293 cells. SC2 antibodies 3705, 3417, 3387, and 3396 all showed neutralization of SARS-CoV-2 in this in vitro assay. In this assay, the SC2 antibody 3705 showed 100% neutralization of infection, SC2 antibody 3417 showed about 70% neutralization, SC2 antibody 3396 showed about 50% neutralization, and SC2 antibody 3387 showed about 45% neutralization.
[179] A bar graph of virus neutralization by SC2 antibodies 3705, 3417 and 3387 is shown in FIG. 2. A line graph showing virus neutralization by SC2 antibodies 3705, 3417, and 3396 is shown in FIG. 3.
Example 6: Binding of Spike Protein Variants by Anti-SARS-CoV-2 Antibodies
[180] Mutant SARS-CoV-2 SI proteins and SARS-CoV-1 S protein were conjugated separately to Luminex beads with EDC-NHS chemistry. SC2 antibody 3387 was incubated with antigen conjugated beads and antibody binding was detected using PE conjugated anti-human Fab antibody and a Luminex 200 instrument.
[181] Spike protein with mutations D614G and E484K (Sweden-1 variant of European variant B- 1), or D614G,V445I,H655Y,and E583D (England/Bristol variant of European variant B-l), or G485S (related to Australia-1 variant), or N501Y (South African variant Bl.1), or S494P, or V483K, or R683A, R685A, F817P, A892P, A899P, A942P, K986P, V987P were tested. Spike protein from Wuhan strains and Omicron strains was also tested.
[182] SC2 antibody 3387 was able to bind each of these mutants spike proteins with affinity similar to that of the wild-type spike protein. SC2 antibody 3387 bound to Omicron with a Kd of 409 pM, and Wuhan with a Kd of 784 pM.
Example 7: Binding of Alpha. Beta, Gamma. Kappa, and Delta Variants by Anti-SARS-CoV-2 Antibodies
[183] Binding of C+SC antibody 3387 to other SARS-CoV-2 variants was assessed as in Example
6. Antigens from the following variants were tested: B.1.1.17 (Alpha) SI, B.1.1.28 (Gamma) S1+S2, 20H/501Y.V2 (Beta) SI, B.1.617 (Kappa) RBD, B.1.617.2 (Delta) RBD, Omicron RBD, Wuhan RBD, S1+S2 S494P, S1+S2 V483A, S1+S2
R683A+R685A+F817P+A892P+A899P+A942P+ K986P+V987P, S1+S2 G485S, S1+S2 D614G, S1+S2 E484K, S1+S2 D614G+V445I+H655Y+E583D, S1+S2 L452R+T478K.
[184] SC2 antibody 3387 was able to bind each of these mutants antigens with affinity similar to that for wild-type antigen. EC50 (half maximal binding) was measured for binding of these variants by SC2 antibody 3387: beta (150 ng/ml); alpha (86 ng/ml); gamma (140 ng/ml); kappa (56 ng/ml); delta (46 ng/ml); omicron (35 ng/ml); and Wuhan (60 ng/ml).
Example 8: Neutralization of Delta Variant by Anti-SARS-CoV-2 Antibodies
[185] An ACE2 expressing HEK293T cell line (“LentiX ACE2.S4”) was constructed by packaging pCMV-AC-GFP (Origene) into lentivirus and transducing HEK293T’s. LentiX ACE2.S4 cells were grown to 85% confluency, and seeded in 96-well plates at 15k cells/well. Anti- SARS-CoV-2 antibody (SC2 antibody 3387) or a nonspecific antibody was added to wells prior to inoculation with SARS-CoV-2 Delta Variant pseudovirus (eEnzyme). The results of this are shown in FIG. 4. SC2 antibody 3387 neutralized the delta variant and greatly reduced infection of cells. Example 9: Neutralization of SARS-CoV-2
[186] Calu-3 cells were grown to confluency, and anti-SARS-CoV-2 antibody was added to the media. 40pL SARS-CoV-2 virus at a target MOI of 0.05 was added to the Calu-3 cells. After 24 hours, the supernatant was removed for TCID50 assays. Vero E6 cells were seeded at 10k cells in lOOpL per well. Infected cell culture supernatant was diluted with 950 pL D10 media, and then serial diluted. After 72 hours, wells with complete cytopathic effect were counted.
[187] Full length IgGl formatted AUG-3387 and its ScFv formatted version, AUG-3705, were tested for neutralization activity. AUG-3705 demonstrated somewhat higher efficacy in these assays over AUG-3387, indicating the improved avidity of the dimeric IgGl did not improve neutralization enough to compensate for the higher molarity of AUG-3705 at the same concentration. See FIG. 5.
Example 10: Efficacy of Anti-SARS-CoV-2 Antibodies in Hamsters
[188] Group 1 male, Syrian Golden Hamsters received a single IP administration of sterile saline solution. Syrian Hamsters in Groups 3 and 4 received a single IP administration of SC2 antibody
3387 solution. 24-48 hours later the Hamsters were inoculated with SARS-CoV-2 (Wuhan-1), and four days after inoculation the viral load in the Hamsters was measured.
[189] The results from the Hamster study are shown in FIG. 6. As the dose of SC2 antibody 3387 antibody is increased, the viral titer of the Wuhan- 1 variant is decreased by 1-2 logs. [190] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
[191] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein.
Such equivalents are intended to be encompassed by the following claims.
Seq Ab Amino Acid Sequence
ID No
99 1
EVQLVESGGGLVQPGGSLRLSCAASGFTLNNYWMHWVRQAPGKGPVWVSRINSDGSSTSYADSVKGRF
TISRDNAKNTLFLQMNSLRAEDTAVYHCAREVRSAAGYFDYWGQGTLVTVSS
100 1
DIQMTQSPSSVSASVGDRVTITCRASQGISNWLTWYQHKPGTAPKLLIYGASSLQSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCQQANTFPLTFGGGTKVEIK
101 2
EVQLLESGGGLVQPGGSLRLSCAASGFI FSDYAMSWVRQAPGKGLEWVAVINNGGGSVYYADSVKGRF
TISRDNSKNTLHLQMNSLRTDDTAVYYCAKFRGETHLVWYFDRWGRGTLVTVSS
102 2
DIQMTQSPSAMSASVGDRVTITCRATQGFSNYLAWFQQRPGKAPKRLIYATSTLHSGVPSRFSGSGSG
TEFNLTISSLQPEDFATYYCLQHGRYPATFGQGTKLEIK
103 3
QVQLVQSGAEVMQVGASVKVSCTTSGFI FISHYMHWVRQAPGQGLEWMGIITPANTTKYSQRFQGRVT
MTSDASTSTVYMELSSLRSEDTAVYYCAREWGELDSSVFDYWGQGTLVTVSA
104 3
QSVLTQPPSVSGAPGQRVTISCNGSSSNIGAGYDVHWYQHFPGSAPKLLMYGNKNRPSGVPDRISASK
SDSSASLAITGLRGEDEADYYCQSYDNSLSVWVFGGGTKLTVL
105 4
QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWNWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVT
ISVDTSKKQFSLKLSSVTAADTAVYYCARKFEQWGQGTLVTVSS
106 4
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSG
TDFTLTISSLEPEDFAVYYCQQRSNWPTWTFGQGTKVEIK
107 5
EVQLIQSGSEIKKPGESLKISCKGSGYRFSAYWLAWVRQMPGKGLECMGVIYPGDSDTIYNPAFVGQV
TISADKSTNTAYLQWSSLKASDTATYYCARQQGVQLWFANWGRGTLVTVSS
108 5
DIQMTQSPSTLSASVGDRVSITCRASQSISSWLAWYQQKPGKAPNLLIYTASNLESGVPARFSGSGSG
TEFTLTISSLQPDDFATYYCQQYNTYPWTFGQGTKVEVK
109 6
QVQLVQSGAEVKRPGASVKISCKTSGYTFTNYAVHWLRQAPGQGLEWMGWINGGTGHTKYSRKFQGRV
TITRDTSASTAYMEVHSLRSEDTAVFYCAGSPTYYSWFDPWGQGTQVIVSS
110 6
QAVVTQEPSLTVSPGGTVTLTCASSTGAVTSGYYPNWFQQKPGQAPRALIYSTSNKHSWTPARFSGSL
LGGKAALTLSGVQPEDEAEYYCLLYYGGAWVFGGGTKLTVL
111 7
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPGKGLEWVSSISGSGDRIYGVDSLKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARRPLGSRFDLWGRGTLVTVSS
112 7
QSALTQPPSVSGSPGQSITITCTGTSSDVGGYQYVSWYQQHPGKAPKVIIYDVSYRPSGFSNRFSGSK
SGNTASLTISGLQTEDEAEYYCSSYTRSGTYVFGTGTEVTVL
113 8
EVQLLESEGGLVQPGGSLRLSCAASGFI FSDYAMSWVRQAPGKGLEWVAVINNGGGSVYYADSVKGRF
TISRDNSKNTLHLQMNSLRTDDTAVYYCAKFRGETHLVWYFDRWGRGTLVTVSS
114 8
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSG
TEFTLTISSLQPDDFATYYCQQYNSYSPWTFGPGTKVDIK
115 9
QLQLQESGPGLVKPSETLSLTCTVSRGSISSSAYYWGWVRQPPGKGLEWIGSINYNGNTYYTSSLKSR
LTISVDTSRNQFSLKLSSVTAADTAVYYCARIIISGSNWFDPWGQGTLVTVSS
116 9
QAVVTQEPSLTVSPGGTVTLTCASSTGAVTSGYYPNWFQQKPGQAPRALIYSTSNKHSWTPARFSGSL
LGGKAALTLSGVQPEDEAEYYCLLYYGGAWVFGGGTKLTVL
117 10
EVQLIQSGSEIKKPGESLKISCKGSGYRFSAYWLAWVRQMPGKGLECMGVIYPGDSDTIYNPAFVGQV
TISADKSTNTAYLQWSSLKASDTATYYCARQQGVQLWFANWGRGTLVTVSS
118 10
EIVMTQSPATLSVSPGERATLSCRASQSVGNSLAWYQQKPGQPPRLLIYDASTRATGIPASFSGIGSG
TEFTLTISSLQPEDFAAYHCQQYYNWPLTFGGGTKVEIK
119 11
EVQLVQSGAEVKNLGESLKISCKASGYTFTSYWIGWVRQMPGKGLEYMGIVYPGGSDTRYSPSFQGQV
TISADKSISTAYLQWNTLKASDTAMYYCVRAAYGLGGITGPWGQGTLVTVSS
120 11
QSALTQPPSVSGSPGQSITITCTGTSSDVGGYQYVSWYQQHPGKAPKVIIYDVSYRPSGVSNRFSGSK
SGNTASLTISGLQTEDEAEYYCSSYTRSGTYVFGTGTEVTVL
121 12
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCAKAGTYYYDSSGYTHYWGQGTLVTVSS
122 12
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSG
TDFTLTISSLEPEDFAVYYCQQRSNWPTWTFGQGTKVEIK
123 13
EVQLVQSGAEVKKPGESLRISCQGSGYSFTTYWITWVRQMPGKGLEWMGRSDPSDSYSNYSPSFQGRV
IMSFEKSTNTAYLQWTSLKASDTAIYYCARHDISGFYLPNWGQGTLVTVSS
124 13
DVQMTQSPSTLSASVGDRVTITCRASQSITSRLAWYQQKPGKAPKVLIYKASSLESGVPSRFSGSGSG
TEFTLTISSLQPDDFATYYCQQYNSYSLTFGQGTKVEIK
125 14
EVQLVQSGAEVKKPGESLKISCKGSGYRFTNYWIGWVRQMPGKGLEWMGIIYPDESDTRYSPSFQGQV
TISAVKSISTAYLQWRSLKASDTAMYYCARQTDGKSWLDPWGQGTLVTVSS
126 14
DVQMTQSPSTLSASVGDRVTITCRASQSITSRLAWYQQKPGKAPKVLIYKASSLESGVPSRFSGSGSG
TEFTLTISSLQPDDFATYYCQQYNSYSLTFGQGTKVEIK
127 15
EVQLVQSGAEVKKPGESLKISCKGSGYRFTNYWIGWVRQMPGKGLEWMGIIYPDESDTRYSPSFQGQV
TISAVKSISTAYLQWRSLKASDTAMYYCARQTDGKSWLDPWGQGTLVTVSS
128 15
QSVLTQPPSVSAAPGQKVTISCSGSDSNIGKNYVCWYQSLPGTAPKLLMFDNSKRPSGIPDRFSASKS
GTSAALVITGLQTGDEADYYCGTWDSSLYAGVFGGGTRLTVL
129 16
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWDDDKRYSPSLKSR
LTITKDTSKNQVVLTLTNMDPVDTATYYCAHRGPVAGHFGFWGQGTLVTVSS
130 16
QSVLTQPPSVSAAPGQKVTISCSGSDSNIGKNYVCWYQSLPGTAPKLLMFDNSKRPSGIPDRFSASKS
GTSAALVITGLQTGDEADYYCGTWDSSLYAGVFGGGTRLTVL
131 17
QVQLQESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEIYHSGSTNYNPSLKSRV
TISVDKSKNQFSLKLSSVTAADTAVYYCARVLNISWADAFDIWGQGTMVTVSS
132 17
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCQQSYSTPPYTFGQGTKLEIK
133 18
QMQLVESGGGVVQPGRSLRLSCAVSGFTFSNYGMNWVRQAPGKGLEWVADISFDGSERHYADSVKGRF
TISRDNSKNTLYLQMNNLRAEDTAVYYCAKPLIAARPPDSWGQGTLVTVSS
134 18
QSVLTQPPSVSAAPGQKVTISCSGSDSNIGKNYVCWYQSLPGTAPKLLMFDNSKRPSGIPDRFSASKS
GTSAALVITGLQTGDEADYYCGTWDSSLYAGVFGGGTRLTVL
135 19
EVQLLESGGGLVQPGGSLRLSCAASGFI FSDYAMSWVRQAPGKGLEWVAVINNGGGSVYYADSVKGRF
TISRDNSKNTLHLQMNSLRTDDTAVYYCAKFRGETHLVWYFDRWGRGTLVTVSS
136 19
DIQMTQSPSTLSASVGDRVSITCRASQSISSWLAWYQQKPGKAPNLLIYTASNLESGVPARFSGSGSG
TEFTLTISSLQPDDFATYYCQQYNTYPWTFGQGTKVEVK
137 20
EVQLMQSGAQMKKPGESLKISCQGSGYNFPNSWIAWVRQMPGKGLEYMGIIYASNSDTRYSPSFQGQV
SISVDKSISTAYLQWSSLKASDTAMYYCARRADYAFDHWGQGTLVTVSS
138 20
QSVLTQPPSVSAAPGQKVTISCSGSDSNIGKNYVCWYQSLPGTAPKLLMFDNSKRPSGIPDRFSASKS
GTSAALVITGLQTGDEADYYCGTWDSSLYAGVFGGGTRLTVL
139 21
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPGKGLEWVSSISGSGDKIYGVDSLKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARRPLGSRFDLWGRGTLVTVSS
140 21
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK
141 22
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWDDDKRYSPSLKSR
LTITKDTSKNQVVLTLTNMDPVDTATYYCAHRGPVAGHFGFWGQGTLVTVSS
142 22
EIVLTQSPGTLSLSPGERAALSCRASQSLSSTYLAWYQQKPGQAPRLLIYAASSRATGIPDRFSGSGS
GTDFTLTIRRLEPEDFAVYYCQHFGTFGQGTTVEIK
143 23
EVQLVESGGGLVKPGGSLRLSCAASGFTFNSYSMNWVRQAPGKGLEWVSSITSSSSYIYYADSVKGRF
TISRDNAKNSLYLQMNSLRADDTAVYYCARASKQYYYYYYMDVWGKGTTVTVSS
144 23
VIVLTQSPGTLSLSPGDRGTLSCTASQFVRNRDLAWYQQKPGQAPRLLIYGASRRATGIPDRFSGGGS
GTDFTLTISRLEPEDCAVYFCLQYASSPMTFGQGTKVEIK
145 24
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPGKGLEWVSSISGSGDRIYGVDSLKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARRPLGSRFDLWGRGTLVTVSS
146 24
DIQMTQSPSTLSASVGDRVSITCRASQSISSWLAWYQQKPGKAPNLLIYTASNLESGVPARFSGSGSG
TEFTLTISSLQPDDFATYYCQQYNTYPWTFGQGTKVEVK
147 25
EVQLMQSGAQMKKPGESLKISCQGSGYNFPNSWIAWVRQMPGKGLEYMGIIYASNSDTRYSPSFQGQV
SISVDKSISTAYLQWSSLKASDTAMYYCARRADYAFDHWGQGTLVTVSS
148 25
EIVLTQSPGTLSLSPGERAALSCRASQSLSSTYLAWYQQKPGQAPRLLIYAASSRATGIPDRFSGSGS
GTDFTLTIRRLEPEDFAVYYCQHFGTFGQGTTVEIK
149 26
QVQLVQSGAEVMQVGASVKVSCKASEFTFTTYHLHWVRQAPGQGLEWMGIISPTGGSATYAQKFQGRV
TMTRDTSTRTVYMELSSLRSEDTAVYFCARDLGGSYYFDYWGQGTLVTVSS
150 26
EIVLTQSPATLSLSPGERATLSCRASQSLSTYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSG
TDFSLTISSLEPEDFAVYYCQQRSDWPRTFGQGTKLEIK
151 27
QVQLQESGPRLVKPSQTLSLTCTVSGGSMTRGYFYWSWIRQHPGKGLEWIGSIYHSGTTFYNASLQSR
LAMSIDTSSKQFSLMLTSVTAADTAIYFCARDRTSVVGGGMDPWGQGI LVTVST
152 27
EIVLTQSPATLSLSPGDSATLSCRATHSVSSSYLTWYQQKPGQAPRLLIYGTSIRATGVPARFSGSGS
GTDFTLTISRLEAEDFAVYYCQRYSNSPPMYAFGQGTQLTIK
153 28
QVQLVESGGGVAQPGTSLRLSCEGSGFMFSGHGMHWVRQAPGKGLEWVAVVSAAGGTQYYAESVKGRF
TISRDNSRNTMTLQMNSLRPDDTALYYCTKEGDDSAYLAFDIWGQGTMVTVSS
154 28
ETVLTQSPATLSLSPGERATLSCRASQSIANNLAWYRQKPGQPPRLLIYGASTRATGVPARLTGSGSG
TDFTLTITSLEPEDFAVYYCQHRSHWPPGGTFGQGTKLEIK
155 29
EVQLVQSGAEVKNLGESLKISCKASGYTFTSYWIGWVRQMPGKGLEYMGIVYPGGSDTRYSPSFQGQV
TISADKSISTAYLQWNTLKASDTAMYYCVRAAYGLGGITGPWGQGTLVTVSS
156 29
DVQMTQSPSTLSASVGDRVTITCRASQSITSRLAWYQQKPGKAPKVLIYKASSLESGVPSRFSGSGSG
TEFTLTISSLQPDDFATYYCQQYNSYSLTFGQGTKVEIK
157 30
QVQLVESGGGVVPPGRSLRLSCEGLGFI FSDYTMAWVRQAPGKGLEWGALISHDGSTKRSADSVEGRF
SISRDNSKNLVHLHMDSLRAEDTAVYFCVRDHFLRLIREIWDNWGQGTQVTVSS
158 30
QSVLTQPPSVSGAPGQRVTISCNGSSSNIGAGYDVHRYQHFPGSAPKLLMYGNKNRPSGVPDRISASK
SDSSASLAITGLRGEDEADYYCQSYDNSLSVWVFGGGTKLTVL
159 31
EVQLIQSGSEIKKPGESLKISCKGSGYRFSAYWLAWVRQMPGKGLKCMGVIYPGDSDTIYNPAFVGQV
TISADKSTNTAYLQWSSLKASDTATYYCARQQGVQLWXANWGRGTLVTVSS
160 31
DVQMTQSPSTLSASVGDRVTITCRASQSITSRLAWYQQKPGKAPKVLIYKASSLESGVPSRFSGSGSG
TEFTLTISSLQPDDFATYYCQQYNSYSLTFGQGTKVEIK
161 32
EVQLVQSGAEVKKPGESLKISCKGSGYRFTNYWIGWVRQMPGKGLEWMGIIYPDESDTRYSPSFQGQV
TISAVKSISTAYLQWRSLKASDTAMYYCARQTDGKSWLDPWGQGTLVTVSS
162 32
DIQMTQSPSAMSASVGDRVTITCRATQGFSNYLAWFQQRPGKAPKRLIYATSTLHSGVPSRFSGSGSG
TEFNLTISSLQPEDFATYYCLQHGRYPATFGQGTKLEIK
163 33
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPGKGLEWVSSISGSGDRIYGVDSLKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARRPLGSRFDLWGRGTLVTVSS
164 33
QAVVTQEPSLTVSPGGTVTLTCASSTGAVTSGYYPNWFQQKPGQAPRALIYSTSNKHSWTPARFSGSL
LGGKAALTLSGVQPEDEAEYYCLLYYGGAWVFGGGTKLTVL
165 34
EVQLVESGGGLVQPGGSLRLSCAASGFSFNYDWMHWVRQAPGEGPVWVSCINGDGSTIRYGESVKGRF
TISRDNAKNTLYLQMNSLRLEDTAVYFCVRGAGYI LSYWGPGTVVTVSS
166 34
EVVLTQSPATLSFSPGERATLSCRASQYVSTSVSWYQHRPGQAPRLLFFDVSRRATGIPDRFNGSGSG
TAFNLTISSLEPEDLAVYYCHQRYNWPATFGPGTKVEIK
167 35
QVQLVQSGAEVMQVGASVKVSCKASEFTFTTYHLHWVRQAPGQGLEWMGIISPTGGSATYAQKFQGRV
TMTRDTSTRTVYMELSSLRSEDTAVYFCARDLGGSYYFDYWGQGTLVTVSS
168 35
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSG
TDFTLTISSLEPEDFAVYYCQQRSNWPPALTFGGGTKVEIK
169 36
EVQLVESGGGLVQPGGSLRLSCAASGFSFNYDWMHWVRQAPGEGPVWVSCINGDGSTIRYGESVKGRF
TISRDNAKNTLYLQMNSLRLEDTAVYFCVRGAGYI LSYWGPGTVVTVSS
170 36
EIVLTQSPGTLSLSPGERAALSCRASQSLSSTYLAWYQQKPGQAPRLLIYAASSRATGIPDRFSGSGS
GTDFTLTIRRLEPEDFAVYYCQHFGTFGQGTTVEIK
171 37
EVQLIQSGSEIKKPGESLKISCKGSGYRFSAYWLAWVRQMPGKGLECMGVIYPGDSDTIYNPAFVGQV
TISADKSTNTAYLQWSSLKASDTATYYCARQQGVQLWFANWGRGTLVTVSS
172 37
QSVLTQPPSVSAAPGQKVTISCSGSDSNIGKNYVCWYQSLPGTAPKLLMFDNSKRPSGIPDRFSASKS
GTSAALVITGLQTGDEADYYCGTWDSSLYAGVFGGGTRLTVL
173 38
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPGKGLEWVSSISGSGDRIYGVDSLKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARRPLGSRFDLWGRGTLVTVSS
174 38
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPQTFGQGTKVEIK
175 39
EVQLVESGGGLVQPGGSLRLSCAASGFSFNYDWMHWVRQAPGEGPVWVSCINGDGSTIRYGESVKGRF
TISRDNAKNTLYLQMNSLRLEDTAVYFCVRGAGYI LSYWGPGTVVTVSS
176 39
QSVLTQPPSVSAAPGQKVTISCSGSDSNIGKNYVCWYQSLPGTAPKLLMFDNSKRPSGIPDRFSASKS
GTSAALVITGLQTGDEADYYCGTWDSSLYAGVFGGGTRLTVL
177 40
EVQLVQSGAEVKKPGESLRISCKGSGYSFTSYWINWVRQMPGKGLLEWVGRIDPTDSYTNYSPSFQGH
VSISADKSISTAYLQWSSLKASDTAMYYCARHSDFWSGYPDVWGKGTTVTVSS
178 40
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSG
TEFTLTISSLQPDDFATYYCQQYNSYSPTFGQGTKVEIK
179 41
QVQLVQSGAEVKRPGASVKISCKTSGYTFTNYAVHWLRQAPGQGLEWMGWINGGTGHTKYSRKFQGRV
TITRDTSASTAYMEVHSLRSEDTAVFYCAGSPTYYSWFDPWGQGTQVIVSS
180 41
DIQMTQSPSAMSASVGDRVTITCRATQGFSNYLAWFQQRPGKAPKRLIYATSTLHSGVPSRFSGSGSG
TEFNLTISSLQPEDFATYYCLQHGRYPATFGQGTKLEIK
181 42
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWDDDKRYSPSLKSR
LTITKDTSKNQVVLTLTNMDPVDTATYYCAHRGPVAGHFGFWGQGTLVTVSS
182 42
DIQMTQSPSTLSASVGDRVSITCRASQSISSWLAWYQQKPGKAPNLLIYTASNLESGVPARFSGSGSG
TEFTLTISSLQPDDFATYYCQQYNTYPWTFGQGTKVEVK
183 43
QVQLVQSGAEVMQVGASVKVSCKASAYKSTTYGIIWARQAPGQGLEFMGWVTPHNGVTKYEQKFQDRI
TITTDTSTGTAYMEMRSLRFDDTAIYYCARFVDSDDYRGWLDPWGRGTLVTVSS
184 43
EVVLTQSPATLSFSPGERATLSCRASQYVSTSVSWYQHRPGQAPRLLFFDVSRRATGIPDRFNGSGSG
TAFNLTISSLEPEDLAVYYCHQRYNWPATFGPGTKVEIK
185 44
EVQLVQSGVEVKKPGESLKISCKVSGYI FSTYWIGWVRQLPGKGLECMGII FPSDSDTSYSAPFQGQV
TISVDKSINTAYLQWSSLKASDTAMYFCARQDSRGIQYWGRGTLVTVSS
186 44
EIVLTQSPATLSLSPGERATLSCRSSQSVGRYLAWYQQKPGQAPRLLVYDSSARATGIPARFSGSGSE
TDFTLTINSLEPEDFAVYYCQQRSNWPLTFGGGTKVEFK
187 45
EVQLMQSGAQMKKPGESLKISCQGSGYNFPNSWIAWVRQMPGKGLEYMGIIYASNSDTRYSPSFQGQV
SISVDKSISTAYLQWSSLKASDTAMYYCARRADYAFDHWGQGTLVTVSS
188 45
DIQMTQSPSTVSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLISRASRLESGVPSRFSGSGSG
TEFTLTISSLQPDDCATYYCQQYNYYSFGQGTKVEIR
189 46
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWDDDKRYSPSLKSR
LTITKDTSKNQVVLTLTNMDPVDTATYYCAHRGPVAGHFGFWGQGTLVTVSS
190 46
DIQMTQSPSTVSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLISRASRLESGVPSRFSGSGSG
TEFTLTISSLQPDDCATYYCQQYNYYSFGQGTKVEIR
191 47
QITLKESGPTLVKPTQTLTLTCTFSGFSFTTTGVGVGWIRQPPGKALEWLALINWDDDKRYSPSLKSR
LTITKDTSKNQVVLTMTNMDHADTATYYCAHRRPYPSFEYWGQGTLVTVSS
192 47
DIQLTQSPSFLSASIGDRVTITCRASQGISRFLAWYQQKPGKAPKLLIYGASNLQSGVPSRFSGSGSG
TEFTLTINSLHPEDFATYYCQQLKSYPYTFGQGTKLDIK
193 48
EVQLMQSGAQMKKPGESLKISCQGSGYNFPNSWIAWVRQMPGKGLEYMGIIYASNSDTRYSPSFQGQV
SISVDKSISTAYLQWSSLKASDTAMYYCARRADYAFDHWGQGTLVTVSS
194 48
DIQMTQSPSAMSASVGDRVTITCRATQGFSNYLAWFQQRPGKAPKRLIYATSTLHSGVPSRFSGSGSG
TEFNLTISSLQPEDFATYYCLQHGRYPATFGQGTKLEIK
195 49
EVQLVQSGAEVKKPGESLKISCKGSGYRFTNYWIGWVRQMPGKGLEWMGIIYPDESDTRYSPSFQGQV
TISAVKSISTAYLQWRSLKASDTAMYYCARQTDGKSWLDPWGQGTLVTVSS
196 49
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVSNRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCSSYTSSPRVFGTGTKVTVL
197 50
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWDDDKRYSPSLKSR
LTITKDTSKNQVVLTLTNMDPVDTATYYCAHRGPVAGHFGFWGQGTLVTVSS
198 50
GIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRGTGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCHQYGSSPFI FGPGTKVDIK
199 51
EVQLVESGGGWTGPGGSLRLSCVTSGFTFSSYEMTWVRQAPGRGLEYISYIDTDARRI LYADSVKGRF
AISRDDAKNSLYLQMNSLRAEDTAVYYCARDAEHNYGPVFDYWGQGI LVSVSS
200 51
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSLYTFGQGTKLEIK
201 52
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPGKGLEWVSSISGSGDRIYGVDSLKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARRPLGSRFDLWGRGTLVTVSS
202 52
EIVMTQSPATLSVSPGERATLSCRASQSVGNSLAWYQQKPGQPPRLLIYDASTRATGIPASFSGIGSG
TEFTLTISSLQPEDFAAYHCQQYYNWPLTFGGGTKVEIK
203 53
EVQLVQSGAEVKKPGESLKISCKGSGYRFTNYWIGWVRQMPGKGLEWMGIIYPDESDTRYSPSFQGQV
TISAVKSISTAYLQWRSLKASDTAMYYCARQTDGKSWLDPWGQGTLVTVSS
204 53
EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIAARFSGSGSG
TEFTLTISSLQSEDVAVYYCQQYNNWPVITFGPGTKVDIR
205 54
EVQLVQSGAEVKKPGESLKISCKGSGYRFTNYWIGWVRQMPGKGLEWMGIIYPDESDTRYSPSFQGQV
TISAVKSISTAYLQWRSLKASDTAMYYCARQTDGKSWLDPWGQGTLVTVSS
206 54
EIVLTQSPATLSLSPGERATLSCRATESVGSYVAWYQQRPGQAPRLLIHDVSHRATGVPARFSGSGSE
TDFTLTISSLEPEDFAIYYCQQRTDLFTFGPGTKVEIT
207 55
QVQLQESGPGLVKPSQTLSVTCSVSGASITSDDYYWSWIRQSPGQGLEWIGYISNTGNTYYNPSLKSR
LTISPDTSKNQISLMLTSVTAADTAVYFCVRVRREWQLPGGGCLDYWGQGALVTVSS
208 55
QSALTQPASVSGSPGQSITISCTGSSSNVGSYNLVSWYQQYPGEAPKLMIYEVTKRPSGVSTRFSGSK
SGNTASLTISGLQAEDETDYYCCSYAGSSTYVFGTGTKVTVL
209 56
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRF
TISRDNAKNSLYLQMNSLRAEDTAVYYCARGIVPAAIYYGMDVWGQGTTVTVSS
210 56
DIQMTQSPSSLSASVGDRVTITCRASQTI FRFVNWYQHKPGRAPNVLIYAASSLRSGVPSRFSGAGSG
TEFTLTISSLQPEDFATYYCQQSYTTPWTFGQGTHVDIK
211 57
EVQLVQSGAEVKKPGESLKISCQTSGYNFINYWIGWVRQMPGEGLEWMGIIYPGDSDSRYSPSFQGQV
TISADKSINTAYLQWSSLKASDTAIYYCARLVDTAMINAFDIWGQGTMVIVSS
212 57
EIVLTQSPSTLSLSPGERATLSCRASQSVLSNYFAWYQQKHGQAPRLLIYGASRRATGIPDRFSGSGS
GTDFALTISRLEPEDFAMYYCQLYGFSYPFGQGTKLEVK
213 58
QVQLVQSGAEVMQVGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWINTYNGNTNYAQKLQGRV
TMTTDTSTTTAYMELRSLRSDDTAVYYCARVAVGYCSGGSCYYFDYWGQGTLVTVSS
214 58
SYELTQPPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVLVIYQDSKRPSGIPERFSGSNSGN
TATLTISGTQAMDEADYYCQAWDSSTVVFGGGTKLTVL
215 59
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQV
TISADKSISTAYLQWSSLKASDTAMYYCARLQWLRDGGDFDYWGQGTLVTVSS
216 59
ETVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYAASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSFTFGPGTKVEIK
217 60
QVQLQQWGAGLLKPSETLSLTCAVYGGSVSGYYWSWIRQPPGKGLQWIGEINHSGSTNYSPSLRSRVT
I LLDTSKKQFSLKLSSVTAADTAVYYCARGRSETYGVPERVRLDPWGQGTLVTVSS
218 60
DIQMTQSPSTVSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLISRASRLESGVPSRFSGSGSG
TEFTLTISSLQPDDCATYYCQQYNYYSFGQGTKVEIR
219 61
EVQLMQSGAQMKKPGESLKISCQGSGYNFPNSWIAWVRQMPGKGLEYMGIIYASNSDTRYSPSFQGQV
SISVDKSISTAYLQWSSLKASDTAMYYCARRADYAFDHWGQGTLVTVSS
220 61
EIVLTQSPATLSVSPGDRATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSG
TEFTLTISSLQSEDFAVYYCQQYNDWPPMYTFGQGTKLEIK
221 62
QVQLQESGPGLVKPSQTLSVTCSVSGASITSDDYYWSWIRQSPGQGLEWIGYISNTGNTYYNPSLKSR
LTISPDTSKNQISLMLTSVTAADTAVYFCVRVRREWQLPGGGCLDYWGQGALVTVSS
222 62
DIQMTQSPSTVSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLISRASRLESGVPSRFSGSGSG
TEFTLTISSLQPDDCATYYCQQYNYYSFGQGTKVEIR
223 63
QVLLVESGGGLVKPGGSLRLSCTASGFTFSDYYMIWIRQAPGKGLEWISSISSRSTYIKYADSVKGRF
TISRDNAKNSLYLQMNSLRVEDTAVYYCASGKQWLVGIYDFDSWGQGTLVTVSS
224 63
DIQMTQSPSSLSASVGDRVTITCRASHNIGIWLAWYQQKPGKGPKLLIHRASTLENGVPSRFSGSRSG
TEFTLTITSLQPDDFATYYCQQYNSYLYTFGQGTKLEIK
225 64
QVQLQQWGAGLLKPSETLSLTCAVYGGSVSGYYWSWIRQPPGKGLQWIGEINHSGSTNYSPSLRSRVT
I LLDTSKKQFSLKLSSVTAADTAVYYCARGRSETYGVPERVRLDPWGQGTLVTVSS
226 64
DIQMTQSPSSLSASVGDRVTITCRASHNIGIWLAWYQQKPGKGPKLLIHRASTLENGVPSRFSGSRSG
TEFTLTITSLQPDDFATYYCQQYNSYLYTFGQGTKLEIK
227 65
QVQLVQSGAEVMQVGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWINTYNGNTNYAQKLQGRV
TMTTDTSTTTAYMELRSLRSDDTAVYYCARVAVGYCSGGSCYYFDYWGQGTLVTVSS
228 65
DIQMTQSPSTVSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLISRASRLESGVPSRFSGSGSG
TEFTLTISSLQPDDCATYYCQQYNYYSFGQGTKVEIR
229 66
EVQLVESGGGLVKPGGSLKLSCAASGFNLHSYTMNWVRQAPGKGLEWVSFITSDSRKTFYADSVRGRF
TISRDNAKNSLFLQMNSLRAEDTAVYYCARGVEWDTSTNWFASWGQGTLVTVSS
230 66
EIVMTQSPATLSVSPGERATLSCRASQSVGNSLAWYQQKPGQPPRLLIYDASTRATGIPASFSGIGPG
TEFTLTISSLQPEDFAAYHCQQYYNWPLTFGGGTKVEIK
231 67
QVQLQESGPGLVKPSGTLSLTCAVSGDSISSSHWWSWVRQPPGKGLEWIGEIYHSGSTNYNPSLKSRV
TISRDKSKNHFSLKLNSVTAADTAVYFCARRPLNMMFDFWGQGTLVNVSS
232 67
EIVLTQSPATLSLSPGERATLSCRASRSVSTYLAWYQQKPGQAPRLLIYDASNRASGIPSRFSGSGSG
TDFTLTISSLEPEDFAVYYCQQCYSGPPWTFGQGTKVENK
233 68
EVHLSESGGGLIHPGGSLRLSCAASGFSFRSYAMAWARQAPGKGLEWVSCINGVGGYIHYADSVRGRF
TISRDNSINTLYLQMDSLRVEDTAVYYCAKWGPYSGSQYFEYWGQGTLLSVSS
234 68
EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSG
TEFTLTISSLQSEDFAVYYCQQYNNWPPLTFGGGTKVEIK
235 69
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWDDDKRYSPSLKSR
LTITKDTSKNQVVLTLTNMDPVDTATYYCAHRGPVAGHFGFWGQGTLVTVSS
236 69
QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVYWYQQLPGTAPKLLIYRNNQRPSGVPDRFSGSKS
GTSASLAISGLRSEDEADYYCAAWDDSLSGYWVFGGGTKLTVL
237 70
QINLKESGPPLVKPTQTLTLICTFSGFSLSTRGVYWGWIRHPPGKALEWIAFVYYTDDTRYNPSLKSR
LTISVDTSKNQLSLKLSTVNAVDTAVYYCARGSKLAGHSGYWGQGTLVTVSS
238 70
DIQMTQSPSSLSASVGDRVTITCRASHNIGIWLAWYQQKPGKGPKLLIHRASTLENGVPSRFSGSRSG
TEFTLTITSLQPDDFATYYCQQYNSYLYTFGQGTKLEIK
239 71
QVQLVQSGAEVMQVGASVRVSCKASGYTFISYGISWVRQAPGQGLEWMGWISAYNDNTKYAQKLQGRV
TLTTDTSTSTAYMELRSLRSDDTAVYYCARDGGSYGWGYWGQGTLVTVSS
240 71
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSLTFGGGTKVEIK
241 72
EVQLVESGGGLVQPGGSLRLSCAASGFTLNNYWMHWVRQAPGKGPVWVSRINSDGSSTSYADSVKGRF
TISRDNAKNTLFLQMNSLRAEDTAVYHCAREVRSAAGYFDYWGQGTLVTVSS
242 72
EIVLTQSPATLSLSLGERATLSCRASQTVRSNYLAWYQQKPGLAPRLLIYDASIRVAGIPDRFTGSGS
GTDFTLTISRLEPEDFAVYYCQQFGASPPALTFGGGTKVEIR
243 73
EVQLVESGGGLVQPGGSLRLSCAASGFTLNNYWMHWVRQAPGKGPVWVSRINSDGSSTSYADSVKGRF
TISRDNAKNTLFLQMNSLRAEDTAVYHCAREVRSAAGYFDYWGQGTLVTVSS
244 73
QSALTQPPSVSGSPGQSITITCTGTSSDVGGYQYVSWYQQHPGKAPKVIIYDVSYRPSGVSNRFSGSK
SGNTASLTISGLQTEDEAEYYCSSYTRSGTYVFGTGTEVTVL
245 74
QVQLVQSGAEVREPGSSVKVSCKASGDTLSNSAISWVRQAPGQGLEWMGRIIPMFGMASYSQKFQGRI
TISADKSTRTVYMELSSLTSEDTAVYYCARGGGTWAPFDPWGQGTQLTVSS
246 74
QSVLTQPPSASGTPGQRVTISCSGSGSNIGNNFVYWYQQLPGTAPKLLIYRIDQRPSGVPDRFSGSKS
GTSASLAISGLRSEDEADYYCAAWDDSLSGPVFGGGTKLTVL
247 75
QVLLVESGGGLVKPGGSLRLSCTASGFTFSDYYMIWIRQAPGKGLEWISSISSRSTYIKYADSVKGRF
TISRDNAKNSLYLQMNSLRVEDTAVYYCASGKQWLVGIYDFDSWGQGTLVTVSS
248 75
EIVLTQSPATLSLSPGERANLSCRASQSVNRYLAWYQQKPGQAPRLLIYDASNRATGVPVRFNGSGSG
TDFTLTISSLEPEDFAVYYCQQRTNWPLTFGGGTKVEIK
249 76
QVLLQESGPGLVKASETLSLTCTVSNGSINTSSYYWNWFRQPPGKGLEWIGTIYYTGDTYYSASLKSR
VTISIHRSKSQFSLKLSTVTAADTAVYYCARDPYNWNLFVADSFDVWGLGTMVTVSS
250 76
DIQMTQSPSTLSASVGDRVTITCRASQRISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSG
TEFTLTISSLQPDDFATYYCQQYHSYSWTFGQGTKVEIK
251 77
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLECVSYISSSSSTIYYADSVKGRF
TISRDNAKNTLYLQMNSLGAEDTAVYYCASLYDTXI LWGQGTLVTVSS
252 77
QSALTQPASVSGSPGQSITIPCTGTSSDVGSYNHVSWYQQHPGKAPKLIIYEVSMRPSGVSNRFSGSK
SGNTASLTISGLQTEDEADYYCCSYGGDVYVWVIGGGTKLTVL
253 78
EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYSMNWVRQAPGKGLEWVSSISGGSTYIYYADSLKGRF
TISRDNAKNSLYLQMNSLSAEDTAVYYCAKPLAAAGLLALDFWGQGTQVTVSS
254 78
QSVLTQPASVSGSPGQSITISCTGTISDFGGYNYVSWYQHHPGKAPKLIIYEVSSRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCNSYTSSGTRVFGGGTKLTVL
255 79
QVQLVQSGAEVMQVGASVRVSCKASGYTFTNHPIDWVRQAPGQGLEWMGIINPSGGGVRFAQKFQGRV
TLTTDTSTSTVYMELSSLTSDDTAVYFCARGAGRDVYKSI LAWFDYWGQGTLVTVSS
256 79
DIQMTQSPSSVSASVGDRVTITCRASQGISNWLTWYQHKPGTAPKLLIYGASSLQSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCQQANTFPLTFGGGTKVEIK
257 80
EVQLVESGGGLVQPGGSLRLSCAASGFTLNNYWMHWVRQAPGKGPVWVSRINSDGSSTSYADSVKGRF
TISRDNAKNTLFLQMNSLRAEDTAVYHCAREVRSAAGYFDYWGQGTLVTVSS
258 80
DIVLTQSPGTLSLSPGESATLSCRASQSVNNDYIAWYQQKPGQAPRLLIYGASSRASGIPDRFDGSGS
GTDFTLTIRRLEPDDFAVYYCHQYITLPLTFGGGSKVEIR
259 81
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRF
TISRDNAKNSLYLQMNSLRAEDTAVYYCARGIVPAAIYYGMDVWGQGTTVTVSS
260 81
EIVLTQSPATLSLSPGERATLSCRASRSVSTYLAWYQQKPGQAPRLLIYDASNRASGIPSRFSGSGSG
TDFTLTISSLEPEDFAVYYCQQCYSGPPWTFGQGTKVENK
261 82 EVQLEQSGAEVKKPGESLKISCKVSGYI FTAHWISWVRQMPGKGLEWMGRIDPNESYANYNPSFEGHV
TLSTDKSTDTAYLQWSSLKASDTAIYYCVRQWDGRTTGARGWYHYYHMDFWGTGTAVTVST
262 82
SYELTQPSSVSVSPGQTARITCSGDVLAKKYARWFQQKPGQAPVLVIYKDSERPSGIPERFSGSSSGT
TVTLTISGAQVEDEADYYCYSAADNNWVFGGGTKLTVL
263 83 QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWDDDKRYSPSLKSR
LTITKDTSKNQVVLTLTNMDPVDTATYYCAHRGPVAGHFGFWGQGTLVTVSS
264 83
EIVLTQSPGTLSLSPGERATLSCRASQSVSTRHLAWYQQKPGQAPRLLIYAASRRATGIPDRFSGSGS
GTDFTLTISSLEPEDFAVYYCQQYGTSPYTFGQGTKLEIK
265 84
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYEMNWVRQSPGKGLEWVSYISGSGGTIYYADSVKGRF
TISRDNAKNSLYLQMNSLRAEDTAVYYCARDRSISWTYYYYYMDVWGKGNPGHRLL
266 84 EIVLTQSPATLSLSPGERATLSCRASRSVSTYLAWYQQKPGQAPRLLIYDASNRASGIPSRFSGSGSG
TDFTLTISSLEPEDFAVYYCQQCYSGPPWTFGQGTKVENK
267 85
EVQLVESGGGLVKPGGSLRLSCAASGFSLRSYSMNWVRLAPGKGLERVSSISSSRSYLYYADSVKGRF
TISRDNAKNSLYLQMNSLRAEDTAVYYCARDQEFNYYDSSGHFDYWGQGTLVTVSS
268 85 EIVMTQSPGTLSVSPGEGATLSCRASQSVGSKLAWYQQKQGQAPRLLIYGASTRATGTPARFSGSGSG
TEFTLTISSLQSEDFAVYYCQQYDNWPPYTFGQGTKLQIN
269 86
EVQLVESGGSLVKPGGSLRLSCVGSGFTFSNYSMNWVRQAPGRGLEWVSSISSSDYIYYSDSVKGRFT
ISRDSAKNSVYLHMDGLRPEDTAVYFCASAPEGLNVLRAFGVVTPTNYYFLGMDVWGRGTTVTVSS
270 86
EIVMTQSPATLSVSPGERATLSCRASQSVSTNLAWYQQKPGQAPRLLVYGPSTRATGIPARFSGSGSG
TEFTLTISSLQSEDFAIYYCKHYYNRPPYTFGQGTRVEIK
271 87 QVQLVQSGAEVRKPGSSTKVSCKASGGTFTSYGISWVRQAPRQGLEWLGGIIPLFDTTNYAQKFQGRV
TITADRSTSTAYMELCRLRSEDTAVYYCATLSLRTPVPYDFWSKYWGQGTLVTVSS
272 87 EIVLTQSPGTLSLSPGERVTLSCRASQSVSSSYLAWYQQKPGQAPSLLIYDASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYHCQQYGTSPGTFGQGTKVEIK
273 88
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDSDTRYRPSLQGQV
TISADKSISTAYLQWSSLKASDTAIYYCARQMGRIWPHDAFDIWGRGTMVTVSS
274 88
EIVLTQSPGTLSLSPGERTTLSCRASQTVSNNYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDSAVYYCQQYAGSLPTFGGGTKVEIK
275 89
EVQLVQSGAEVKKPGESLRISCQGSGYSFTTYWITWVRQMPGKGLEWMGRSDPSDSYSNYSPSFQGRV
IMSFEKSTNTAYLQWTSLKASDTAIYYCARHDISGFYLPNWGQGTLVTVSS
276 89
DIQMTQSPSTLSASVEDRVTITCRASQSINKWVAWYQQKPGKAPI LLIYDASNLQTGVPSRFSGSGSG
TEFSLAISSLQPDDFATYYCQQYQSYPYTFGQGTKLEIK
277 90 QLQLQESGPGLVKPSETLSLTCTVSGGSINSDSYYWGWIRQPPGKGLEWIGTI FYSGSTYYNPSLKSR
VTLSVDTSKNQFSLKLNSVTAADTALYYCATHPPTLAARPWDHWGQGTLVTVSS
278 90
EIVLTQSPGTLSLSPGERTTLSCRASQTVSNNYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDSAVYYCQQYAGSLPTFGGGTKVEIK
279 91
EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYSMNWVRQAPGKGLEWVSSISGGSTYIYYADSLKGRF
TISRDNAKNSLYLQMNSLSAEDTAVYYCAKPLAAAGLLALDFWGQGTQVTVSS
280 91
EIVLTQSPGTLSLSPGERVTLSCRASQSVSSSYLAWYQQKPGQAPSLLIYDASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYHCQQYGTSPGTFGQGTKVEIK
281 92
QVQLEDLGAEVRKPGSSVKVSCKASGGTFTSYGISWVRQAPGQGLEWLGGIIPLFDTTNYAQKFQGRV
TITADRSTSTAYMELSRLRSEDTAVYYCATLSLRTPVPYDFWXKYWGQGTLVTVSS
282 92
EIVLTQSPGTLSLSPGERVTLSCRASQSVSSSYLAWYQQKPGQAPSLLIYDASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYHCQQYGTSPGTFGQGTKVEIK
283 93
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWDDDKRYSPSLKSR
LTITKDTSKNQVVLTLTNMDPVDTATYYCAHRGPVAGHFGFWGQGTLVTVSS
284 93
DIQMTQSPSSVSASVGDRVIITCRASQYISSELVWYQQKPGKAPKVLIYAASNLQSGVPSRFSGSGSG
TDFTLTIRGLQLEDCATYYCQQANTFLTFGPGTMVDIK
285 94
EVQLVQSGAEVKKPGESLRISCQGSGYSFTTYWITWVRQMPGKGLEWMGRSDPSDSYSNYSPSFQGRV
IMSFEKSTNTAYLQWTSLKASDTAIYYCARHDISGFYLPNWGQGTLVTVSS
286 94
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKAGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYFCQRYDTSQGTFGQGTKLDIK
287 95
EVQLIQSGSEIKKPGESLKISCKGSGYRFSAYWLAWVRQMPGKGLECMGVIYPGDSDTIYNPAFVGQV
TISADKSTNTAYLQWSSLKASDTATYYCARQQGVQLWFANWGRGTLVTVSS
288 95
KIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPWLLIYGAVSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPYTFGQGTKLEIK
289 96
QVQLVESGGSVVQPGRSLRLSCVAPGFTFSKSAIHWVRPAAGKVLELVAVVTYDGGAKYYADSVKGRF
TISRDNSENTLYLQMNSLRPEDTAVYFCAREWNYDSSPTYDFWGQGTLVTVSS
290 96
EIVMTQSPGTLSVSPGEGATLSCRASQSVGSKLAWYQQKQGQAPRLLIYDASTRATGTPARFSGSGSG
TEFTLTISSLQSEDFAVYYCQQYDNWPPYTFGQGTKLQIN
291 97
QVQLVQSGAEVMQVGASVKVSCKASAYKSTTYGIIWARQAPGQGLEFMGWVTPHNGVTKYEQKFQDRI
TITTDTSTGTAYMEMRSLRFDDTAIYYCARFVDSDDYRGWLDPWGRGTLVTVSS
292 97
QSALTQPASVSGSPGQSITISCTGTSSDFGGYNSVSWYQHHPGKAPKLIIYDVSNRPSGVPDRFSGSK
SGNTASLTISGLQAEDEADYYCSSYTGSAPLYVFGIGTKVTVL
293 98
EVQLVESGGGLVKPGGSLRLSCAASGFTFSYYTVTWVRQAPGKGLEWVSSISSSSSYIIYADSVKGRF
TMSRDNAKNSLYLQMNSLRAEDTAVYYCARDHYYDSSGYYYEVGMDVWGQGTTVTVSS
294 98
KIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPWLLIYGAVSRATGIPDRFSGSGS
GTDFTLTISRLEPEDSAVYYCQQYGGSLPTFGGGTKVEIK
295 99
QVQLEDLGAEVRKPGSSVKVSCKASGGTFTSYGISWVRQAPGQGLEWLGGIIPLFDTTNYAQKFQGRV
TITADRSTSTAYMELSRLRSEDTAVYYCATLSLRTPVPYDFWXKYWGQGTLVTVSS
296 99
DIQMTQSPSTLSASVGDRVTITCRASQSFNGWLAWYQQKPGKAPKLLIYKASNLESGVPSRFSGSGSG
TEFTLTISSLQPDDFATYYCQHYVFGQGTKVEVK
297 100
QVQLVQSGAEVRKPGSSVKVSCKASGGTFTSYGISWVRQAPGQGLEWLGGIIPLFDTTNYAQKFQGRV
TITADRSTSTAYMELSRLRSEDTAVYYCATLSLRTPVPYDFWSKYWGQGTLVTVSS
298 100
EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSG
TEFTLTITSLQSEDFAVYYCQQYNDWPPLTFGGGTKVEIK
299 101
EVQLVQSGAEVKKPGESLRISCQGSGYSFTTYWITWVRQMPGKGLEWMGRSDPSDSYSNYSPSFQGRV
IMSFEKSTNTAYLQWTSLKASDTAIYYCARHDISGFYLPNWGQGTLVTVSS
300 101
EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSG
TEFTLTITSLQSEDFAVYYCQQYNDWPPLTFGGGTKVEIK
301 102
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGRGLDWVAVISYDDSNKYYADSVKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARDQGRPSYYDFWGGYHPSTNLRPVXDYWGQGTLVTVSS
302 102
DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDATNLETGVPSRFSGSGSG
TDFTFTINSLQPEDIATYYCQHYDNLPRVTFGPGTKVDIR
303 103
EVQLLESGGGLVQPGGSLRLSCAASGFTFSNHAMSWVRQAPGKGLEGVSGISHSGRSTYFADSVKGRF
TISRDNSKNTLYLQMNSLRVEDTAVYYCAKVKITI FGMVPXDYWGQGI LVTVSS
304 103
DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDATNLETGVPSRFSGSGSG
TDFTFTINSLQPEDIATYYCQHYDNLPRVTFGPGTKVDIR
305 104
QVQLVAAGGGVDQPGWSLRLSCTASGFTFSTYGMHWVRQAPGKGLGWVGVISYDGRNKYADSVKGRFT
ISRDNSKNTLYLQADTLRPEDTAVYYCARGWAGVTVPGTHEFDYWGRGTVVTVSS
306 104
QAVVTQEPSLTVSPGGTVTLTCGSSTGAVTYSGHFPFWFQQKPGQAPRTLIYDTDNKHSWTPARFSGS
LLGGKAALTLSGAQPDDEADYYCLLAYSDIRI FGGGTKLTVL
307 105
QVQLEDLGAEVRKPGSSVKVSCKASGGTFTSYGISWVRQAPGQGLEWLGGIIPLFDTTNYAQKFQGRV
TITADRSTSTAYMELSRLRSEDTAVYYCATLSLRTPVPYDFWXKYWGQGTLVTVSS
308 105
EIVLTQSPGTLSLSPGERVTLSCRASQSVSSSYLAWYQQKPGQAPSLLIYDASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYHCQQYGTSPGTFGQGTKVEIK
309 106
EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYSMNWVRQAPGKGLEWVSSISGGSTYIYYADSLKGRF
TISRDNAKNSLYLQMNSLSAEDTAVYYCAKPLAAAGLLALDFWGQGTQVTVSS
310 106
EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSG
TEFTLTITSLQSEDFAVYYCQQYNDWPPLTFGGGTKVEIK
311 107
EVQLVQSGAEVKKPGESLRISCQGSGYSFTTYWITWVRQMPGKGLEWMGRSDPSDSYSNYSPSFQGRV
IMSFEKSTNTAYLQWTSLKASDTAIYYCARHDISGFYLPNWGQGTLVTVSS
312 107
DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPSRFSGSGSG
TEFTLTISSLQPEDFATYYCLQHNSYPWTFGQGTKVEIK
313 108
EVQLVQSGAEVKKPGESLRISCQGSGYSFTTYWITWVRQMPGKGLEWMGRSDPSDSYSNYSPSFQGRV
IMSFEKSTNTAYLQGTGLKASDTAIYYCARHDISGFYLPNWGQGTLVTVSS
314 108
AIQLTQSPSSLSASVGDRVTITCRSSLGISSALAWYQQKPGKAPKLLIYHASNLQSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCQQFSSYPITFGGGTKVEIK
315 109
EVQLLESGGGLVQPGGSLRLSCAASGFTFSNHAMSWVRQAPGKGLEGVSGISHSGRSTYFADSVKGRF
TISRDNSKNTLYLQMNSLRVEDTAVYYCAKVKITI FGMVPYDYWGQGI LVTVSS
316 109
QSVLTQPPSVSGAPGQRVTISCTGTSSNIGAGYDVHWYQQLPGTAPKLLDYGNSDRPTGVTDRFSGSR
SGASASLAITGLQAEDEADYYCQSYDRSLSGVVFGGGTKLTVL
317 110
EVQLVQSGTEVKKPGESLKISCKGSGYAFFGYWIGWVRQMPGKGLEWIGLIYPDDSQSRYSPSFQGQV
TMSADKSINTAYLQWGSLRASDSAMYFCARFGGPRLESTYFDYWGQGTLVTVSS
318 110
QSALTQPASVSGSPGQSIAISCSGTSSDVGGYDYVSWYQHHPGKAPRLMISEVSNRPSGVPDRFSGSK
SGNTASLTISGLQAEDESDYYCSSYTSTSTFWVFGGGTKLTVL
319 111
QLQLQESGPGLVKPSETLSLTCTVSGGSINSDSYYWGWIRQPPGKGLEWIGTI FYSGSTYYNPSLKSR
VTLSVDTSKNQFSLKLNSVTAADTALYYCATHPPTLAARPWDHWGQGTLVTVSS
320 111
QAVVTQEPSLTVSPGGTVTLTCGSSTGAVTYSGHFPFWFQQKPGQAPRTLIYDTDNKHSWTPARFSGS
LLGGKAALTLSGAQPDDEADYYCLLAYSDIRI FGGGTKLTVL
321 112
EVLLVESGGGLVQPGGSLRLSCAASGFTFSEHFIDWVRQAPGKGLEWVGRSTNKANRYNTEYAASVKG
RFTISRDDSKNSVYLQMNSLKTEDTAVYYCSRRKVVIHGPSDLWGQGTMVTVSS
322 112
EIVLSQSPGTLSFSPGERATLSCRASQSVRYNYLAWYQQKPGQAPRLLIYHTSIRATGIPDRFRGSGS
GTDFI LTISRLEPEDFAVYYCQHYGASSTFGPGTKVDIK
323 113
EVQLMQSGAQMKKPGESLKISCQGSGYNFPNSWIAWVRQMPGKGLEYMGIIYASNSDTRYSPSFQGQV
SISVDKSISTAYLQWSSLKASDTAMYYCARRADYAFDHWGQGTLVTVSS
324 113
EIVLTQSPGTLSLSPGERVTLSCRASQSVSSSYLAWYQQKPGQAPSLLIYDASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYHCQQYGTSPGTFGQGTKVEIK
325 114
EVQLIQSGSEIKKPGESLKISCKGSGYRFSAYWLAWVRQMPGKGLECMGVIYPGDSDTIYNPAFVGQV
TISADKSTNTAYLQWSSLKASDTATYYCARQQGVQLWFANWGRGTLVTVSS
326 114
QSVLTQPPSVSGAPGQRVTISCTGTSSNIGAGYDVHWYQQLPGTAPKLLDYGNSDRPTGVTDRFSGSR
SGASASLAITGLQAEDEADYYCQSYDRSLSGVVFGGGTKLTVL
327 115
QVQLQESGPGLVKPSGTLSLTCAVSGGSISSTNWWSWVRQPPGKGLEWIGEIYHSGSTNYNPSLKSRV
TISVDKSKNQFSLKVNSVTAADTAVYFCARVQSELDRSSRYSLYYYGMDVWGQGPIGL
328 115
DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPSRFSGSGSG
TEFTLTISSLQPEDFATYYCLQHNSYPWTFGQGTKVEIK
329 116
EVQLVQSGAEVKKPGESLRISCQGSGYSFTTYWITWVRQMPGKGLEWMGRSDPSDSYSNYSPSFQGRV
IMSFEKSTNTAYLQWTSLKASDTAIYYCARHDISGFYLPNWGQGTLVTVSS
330 116
EIVLTQSPGTLSLSPGERTTLSCRASQTVSNNYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDSAVYYCQQYAGSLPTFGGGTKVEIK
331 117
QVQLVESGGGVVQPGRSLRLSCTASGFTFSTYGMHWVRQAPGKGLEWVAVISYDGRNKYADSVKGRFT
ISRDNSKNTLYLQADTLRPEDTAVYYCARGWAGVTVPGTHEFDYWGRGTVVTVSS
332 117
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQRPGKAPKLLIYDASSLESGVPSRFSGSGYG
TEFTLTISGLQPDDFATYYCQHYNNFPESFGQGTRVEIK
333 118
EVQLLESGGGLVQPGGSLRLSCAASGFTFSNHALSWVRQAPGKGLEGVSGISHSGRSTYFADSVKGRF
TISRDNSKNTLYLQMNSLRVEDTAVYYCAKVKITI FGMVPYDYWGQGI LVTVSS
334 118
KIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPWLLIYGAVSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPYTFGQGTKLEIK
335 119
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTTGVGVGWIRQPPEKALECLAFIYWDDDKRYSPSLESR
LTITKGTSENQVVLTMTNMDPVDTATYYCAVIGEQYFGSGSWYFDYWGQGALVSVSS
336 119
EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSG
TEFTLTITSLQSEDFAVYYCQQYNDWPPLTFGGGTKVEIK
337 120
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYVISWVRQAPGQGLEWMGGIIPMFDTTHYTQKFQGRL
TITADESTSTAYMDLSSLRSDDTAVYYCARLIPRNYYDSSGYSSQDYWGQGTLVTVSS
338 120
DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPSRFSGSGSG
TEFTLTISSLQPEDFATYYCLQHNSYPWTFGQGTKVEIK
339 121
QVHLVESGGGVVQPGRSLRLSCAASGFSFSSYGLHWVRQAPGKGLEWVAFISYVGSNKYYADSVKGRF
TISRDNSKNTLYLQMNSLRTEDTAVYYCAREYTVGGI FGFWGQGTLVTVSS
340 121
DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSG
TDFTFTISSLQPEDIATYYCQQYDNLPPFTFGPGTKVDIK
341 122
EVQLVQSGAEGKKPGESLKISCKGSGYDFANQWIGWVRQLPGKGPEWMGIIYPGDSDTRYSPSFQGQV
TISADKSITTAYLHWTSLKASDTAMYYCARHKGSDIATPTRGGFDIWGQGTMVTVSL
342 122
DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGQVPNLLIYAASTLQSGVPSRFSGSGSG
TDFTLTITSLQPEDVATYYCQNYNSAPLTFGGGTKVGIK
343 123
QVQLVESGGGVVQPGRSLRLSCQASGFTFNRYGMHWVRQAPGKGLEWLALIWYDGSEKYYADSVKDRF
TISRDNSKNMLFLQMNNLRAEDTAVYYCAKVTLTSYGDFGHEDYWGQGTLVTVSS
344 123
QSELTQPPSASGTPGQRITISCSGSSSNIGSNYVYWYQQFPGTTPKLLIYRNDQRPSGVPDRLSGSKS
GTSASLAISGLRSEDEADYYCASWDDSVGGPRFGTGTKVTVL
345 124
EVQLVESGGGLVQPGGSLRLSCTAPRFTLSSYSMNWVRQAPGKGLEWVSYISSSSDTMYYADSVKGRF
TISRDNAKNSLFLQMNSLRAEDTAVYYCVTRXFYWGQGTLVTVSS
346 124
QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGAAPKLLIYDNNKRPSGIPDRFSGSKS
GTSATLGITGLQTGDEADYYCGTWDSSLSALFGGGTKLTVL
347 125
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWDDDKRYSPSLKSR
LTITKDTSKNQVVLTLTNMDPVDTATYYCAHRGPVAGHFGFWGQGTLVTVSS
348 125
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSVS
RTDFTLRIHGLESGDFAVYYCQQYGSLPQTFGEGSKVEIR
349 126
EVQLLESGGGLVQPGGSLRLSCAASGFTFNIYAINWVRQAPGKGLEWVSSISGSGDSAYYADSVKGRF
TISRDNSKNTVFLQMNSLTAEDTAVYYCAKQYCTNGVCYTDYYFYNHMDVWGKGTTVTVSS
350 126
DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSG
TDFTFTISSLQPEDIATYYCQQYDNLPPFTFGPGTKVDIK
351 127
EVQLVESGGGLVQPGGSLRLSCAASGFTFSAYLMHWVRQAPGKGLVWVSRVNSDGNDRKYADSVKGRF
IISRDNAKKTIYLQMNSLRAEDTAVYYCANRAGWGQGTLVTVSS
352 127
DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSG
TDFTFTISSLQPEDIATYYCQQYDNLPPFTFGPGTKVDIK
353 128
QVQLEDLGAEVKKPGASVKISCKASGYI FTSYAVHWVRQAPGQRLEWMGWINAGNGETKYSQKFQGRV
TITRDTSASTAYMEMSSLRSEDTAVYYCAREPPYYDFDDYWGQGTLVTVSS
354 128
GIQMTQSPSTLSASVGDRVTITCRASQSMNSWLAWYQQKPGKAPKLLIYEASTLESGVPSRFSGSGSG
TEFTLTISSLQPDDFATYYCQQYNTYSWTFGRGTKVEIK
355 129
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSTYAISWVRQAPGQGLEWMGRIIPI LGIVNYAQKFQGRV
TITADKSTSTAYMELSSLRSEDTAVYYCARGFVGATTDAEMSNWGQGTLVTVSS
356 129
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCQQSYSTPRTFGQGTKVEIK
357 130
EVQLLESGGGLVQPGGSLRLSCVVSGFTFPNSAFSWVRRAPGRGLEWVSTVSANGFSTYYADAVEGRF
TISRDNAKDTLYLQMDTLRVDDTAVYYCAKTAPWVHLWFSPDWDYWGQGSLVTVSS
358 130
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCQQSYSTPWTFGQGTKVEIK
359 131
QVQLVESGGSVVQPGRSLRLSCVASGFTFSKYAMHWVRQAPGKGLEWVAVVTYDGGAKYYADSVKGRF
TISRDNSENTLYLQMNSLRPEDTAVYFCAREWNYDSSPTYDFWGQGTLVTVSS
360 131
QSALTQPASVSGSPGQSITISCTGTSSDIGGYYYVSWYQQHPGQAPKLII FDVSDRPSGISNRFSGSK
SGNTASLTISGLQAEDEAHYFCSSYTSGSTLDVVFGGGTKLTVL
361 132
EVQLIQSGSEIKKPGESLKISCKGSGYRFSAYWLAWVRQMPGKGLECMGVIYPGDSDTIYNPAFVGQV
TISADKSTNTAYLQWSSLKASDTATYYCARQQGVQLWFANWGRGTLVTVSS
362 132
DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSG
TDFTFTISSLQPEDIATYYCQQYDNLPPFTFGPGTKVDIK
363 133
QVQLQESGAGLVKPSQTLSLTCTVSGDSISSGGYYWSWIRQYPGKDLEWIGYIYSSGSTYYNPSLKSG
IIISVDTSKNQFSLKLTSVTAADTAVYYCARDPSSGSHGAAFDIWGQGTMVTVSS
364 133
DIQMTQSPSSLSASVGDRGTITCRASQGIGNDLGWYQQKPGKAPKRLIYAASNLNSGVPSRFSGSGSG
TEFTLTISSLQPEDFATYYCLQHNTYPWTFGQGTKVEIK
365 134
QVQLEDLGAEVKKPGSSVKVSCTASGGTFDRSVIDWVRQAPGQGLEWVGRIIPLYGSANYAQKFHGRL
TI S AD E FTSTAYM E LSS LRS EDTAVYYC AGTT LVN PKAXDYWGQGT LVTVSS
366 134
DIQMTQSPSTLSASVGDTVSITCRASQSFSRWLAWYQQRPGKAPKLLIYQASSLQSGVPSRFSGSGSG
TEFTLTITSLQPDDFATYYCQQYNTYPYTFGQGTKVEIK
367 135
QVQLVQSGAEVKKPGSSVKVSCTASGGTFDRSVIDWVRQAPGQGLEWVGRIIPLYGSANYAQKFHGRL
TISADEFTSTAYMELSSLRSEDTAVYYCAGTTLVNPKAFDYWGQGTLVTVSS
368 135
EIVLTQSPGTLSLSPGERATLSCRASQSVSGNYLAWYQQKPGQAPRLLIYGISTRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYDTSQGTFGQGTKLEIK
369 136
QVQLEDLGAEVKKPGSSVKVSCTASGGTFDRSVIDWVRQAPGQGLEWVGRIIPLYGSANYAQKFHGRL
TI S AD E FTSTAYM E LSS LRS EDTAVYYC AGTT LVN PKAXDYWGQGT LVTVSS
370 136
DIQMTQSPSAMSASVGDRVTITCRASQGISNYLAWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSG
TEFTLTISSLQPEDFATYYCLQHNSYPHTFGQGTKLEIK
371 137
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSTYAISWVRQAPGQGLEWMGRIIPI LGIVNYAQKFQGRV
TITADKSTSTAYMELSSLRSEDTAVYYCARGFVGATTDAEMSNWGQGTLVTVSS
372 137
EVVLTQSPATLSSSPGERVTLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPASSVAVGLG
QTSLSPSAAWSLKI LQFITVCSVATGLRSLSAEGPRWRS
373 138
EVQLVESGGGWTGPGGSLRLSCAASGFI FSDHYMDWVRQAPGKGLEWVGRSWRKTESATPDYAASVRG
RFTISRDDSQNSLYLQMDSLKTEDTAVYYCATSVGDTADFDYWGQGALVTVSS
374 138
DIQMTQSPSTLSASVGDRVTITCRASESISSWLAWYQQKPGEAPKLLMYKSSI LESGVPSTFSGTGSG
TEFTLTISRLQPDDFATYYCQQYNSYPHTFGQGTKLDIK
375 139
QVQLQESGPRLVKPSQTLSLICTVSGVSITSRGVYWNWIRHHPGKGLEWIGYVYYTGDTLYNPSLKSR
LTLSVDTSKNQLSLQLSSVTAADTAVYYCARVSNFARQSDYWGHGTLVTVSS
376 139
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRGTGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCHQYGTSPWTFGQGTKVEIK
377 140
QVQLQQWGAGLLKPSETLSLTCGVYGGSFSGYYWTWIRQSPGKGLEWIGEINHSGSTNYNPSLKSRVS
ISVDTSKKQFSLKLTSVTAADTAVFYCARGYGSGSYDSKSGFDIWGQGTMVTVSS
378 140
DIQLTQSPSFLSASVGDRVTITCRASQGISSSLAWYQQKPGKAPKLVIYAASTLQSGVPSRFSGSGSG
TEFTLTISSLQSEDFATYYCQQVNDIPPYTFGQGTKLEIK
379 141
QVQLQESGPGLVKPSQTLSLTCTVSGDSISSGGYYWSWIRQYPGKGLEWIGYIYSSGSTYYNPSLKSG
IIISVDTSKNQFSLKLTSVTAADTAVYYCARDPSSGSHGAAFDIWGQGTMVTVSS
380 141
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGNNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFS
GSGSGTDFTLKISRVEAEDVGVYYCMQALQTPWTFGQGTKVEIK
381 142
EVQLMQSGAQMKKPGESLKISCQGSGYNFPNSWIAWVRQMPGKGLEYMGIIYASNSDTRYSPSFQGQV
SISVDKSISTAYLQWSSLKASDTAMYYCARRADYAFDHWGQGTLVTVSS
382 142
SYELTQPPSVSVAPGQTARITCGGDNIGSRSVHWYQQQPGQAPVLVVYDDSARRSGIPERFSGSNSGN
TATLTISRVEAGDEADYYCQVWDSFSDHYVFGTGTTVTVL
383 143
QVQLQESGPRLVKPSQTLSLICTVSGVSITSRGVYWNWIRHHPGKGLEWIGYVYYTGDTLYNPSLKSR
LTLSVDTSKNQLSLQLSSVTAADTAVYYCARVSNFARQSDYWGHGTLVTVSS
384 143
SYELTQPPSVSVAPGQTARITCGGDNIGSRSVHWYQQQPGQAPVLVVYDDSARRSGIPERFSGSNSGN
TATLTISRVEAGDEADYYCQVWDSFSDHYVFGTGTTVTVL
385 144
QVQLMQSGAEVKKPGSSLKLSCNISGGTFSSYSVSWVRQAPGQGLEWVGGFITVSDTAHYSQKFQGRV
TITADESGSTVYMDLSGLKSEDTAIYYCAGRFCRSTSCYLQLSRSLSYMDVWGTGTTVTVSS
386 144
DIVLTQSPATLSLSPGERTTLSCRASQSVGTYLAWYQQRPGQTPRLLIYDTSNRATGIPARFSGSGSG
TDFTLTISSLEPEDVAIYYCQQRSSWPLTFGGGTKVEI E
387 145
EVQLVESGGGLIQPGGSLRLSCAPSGFTVSGSYMSWVRQAPGRGLEWVSVI FSGGATYYSDSVKGRFT
ISRDSSKNTLFLQMNNLRAEDTAIYYCARDGGFYGDYAAFDLWGLGTMVTVSS
388 145
EIVLTQSPATLSLSPGERATLSCRASQSVSTYLAWYQQKPGQAPRLLIYDASKRAAGIPARFSGSGSG
TDFTLTISSLEPEDFAVYYCHQRSNWLTFGGGTKVEIK
389 146
EVQLVESGGGLIQPGGSLRLSCAPSGFTVSGSYMSWVRQAPGRGLEWVSVI FSGGATYYSDSVKGRFT
ISRDSSKNTLFLQMNNLRAEDTAIYYCARDGGFYGDYAAFDLWGLGTMVTVSS
390 146
EIVLTQSPGTLSLSPGERATLSCRASQTISSTYLAWYQQRPGQALRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRVEPEDFAVYYCQQYDYSGSLWTFGQGTKVDVK
391 147
EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYWMSWVRQAPGKGLEWVANIKQDGSERYYVGSLKGRF
TISRDNAKNSLFLQMNSLRAEDTAVYYCARDLEGKYSYFDCWGQGTLVTVSS
392 147
SYELTQTPSVSVAPGQTARITCGGNNIGSKSVQWYQQKPGQAPVLVVYDDTVRPSGIPERFSGSNSGS
TATLTISRVEAGDEADYYCQVWDSSTDHLMFGGGTKLTVL
393 148
QMQLVESGGGVVQPGRSLRLSCAASGFTFSNHGIHWVRQAPGKGLEWVAVISSDGSDKYYGDSVKGRF
TISRDNSQNI LYLQMNSLRSEDTAVYYCAKDGGEDLDFWGQGTLVTVSS
394 148
SYELTQPPSVSVAPGQTARITCGGDNIGSRSVHWYQQQPGQAPVLVVYDDSARRSGIPERFSGSNSGN
TATLTISRVEAGDEADYYCQVWDSFSDHYVFGTGTTVTVL
395 149
EVQLEKTGGGLVKPGGSLKLSCAASGFNLHSYTMNWVRQAPGKGLEWVSFITSDSRKTFYADSVRGRF
TISRDNAKNSLFLQMNSLRAEDTAVYYCARGVEWDTSTNWFASWGQGTLVTVSS
396 149
QSALTQPASVSGSPGQSITISCTGTSSDVGSYNLVSWFQQHPGKAPKLMIYEGSKRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCCSYAGSLHVVFGGGTKLTVL
397 150
QVQLVQSGAEVKKPGASVKISCKASGYI FTSYAVHWVRQAPGQRLEWMGWINAGNGETKYSQKFQGRV
TITRDTSASTAYMEMSSLRSEDTAVYYCAREPPYYDFDDYWGQGTLVTVSS
398 150
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSG
TDFTLTISSLEPEDFAIYYCQQRSTWPRTFGQGTRLEIK
399 151
QVQLEDLGAEVKKPGASVKISCKASGYI FTSYAVHWVRQAPGQRLEWMGWINAGNGETKYSQKFQGRV
TITRDTSASTAYMEMSSLRSEDTAVYYCAREPPYYDFXDYWGQGTLVTVSS
400 151
DIQMTQSPSSLSASVGDRVTITCRASHTIRGFLNWYQQKPGKAPNLLIYAGSSLQSGVPPRFSGSASG
TDFTLTISSLQPEDFATYYCQQTYSAPRTFGQGTRVEVK
401 152
QVQLMQSGAEVKKPGSSLKLSCNISGGTFSSYSVSWVRQAPGQGLEWVGGFITVSDTAHYSQKFQGRV
TITADESGSTVYMDLSGLKSEDTAIYYCAGRFCRSTSCYLQLSRSLSYMDVWGTGTTVTVSS
402 152
QSALTQPASVSGSPGQSITISCTGTTSDIGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCSSYTISRTGVLFGGGTKLTVL
403 153
QVQLVESGGGVVQPGRSLRLSCQASGFTFNRYGMHWVRQAPGKGLEWLALIWYDGSEKYYADSVKDRF
TISRDNSKNMLFLQMNNLRAEDTAVYYCAKVTLTSYGDFGHEDYWGQGTLVTVSS
404 153
DLVLTQSPGTLSVFPGESATLSCRASQSLSSTYLAWYQQKPGQPPRLLIYGTSTRATGIPDRFSGSGF
GTDFTLTISGLEPEDFAVYHCQHYGPSHFTFGPGTRVDLK
405 154
EVQLLASRGGLVQPGGSLRLSCEASGFTFSRYPMRLVRQAPGQGLGWVSGISGSGGRTYHADSVKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCAKAGTYYYDSSGYTHYWGQGTLVTVSS
406 154
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSG
TEFTLTISSLQPDDFATYYCQQYNSYPTFGQGTKLEIK
407 155
QVQLVESGGGLVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWFDGSNKFQADSVKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARGTDDFDFWGQGTLVTVSS
408 155
SYELTQTPSVSVAPGQTARITCGGNNIGSKSVQWYQQKPGQAPVLVVYDDTVRPSGIPERFSGSNSGS
TATLTISRVEAGDEADYYCQVWDSSTDHLMFGGGTKLTVL
409 156
QVQLVESGGGLVQPGRSLRLSCAASGFPFSSYGMHWVRQAPGKGLEWVAVIVYDGKSEYYADSVKGRF
TITRDNSRNTVHLQMNSLRAEDTALYYCAKDRSSWYEGLYYYYYGMDVWGQGTAVTVSS
410 156
SYELTQTPSVSVAPGQTARITCGGNNIGSKSVQWYQQKPGQAPVLVVYDDTVRPSGIPERFSGSNSGS
TATLTISRVEAGDEADYYCQVWDSSTDHLMFGGGTKLTVL
411 157
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWFDGSNKFQADSVKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARGTDDXDFWGQGTLVTVSS
412 157
SYELTQTPSVSVAPGQTARITCGGNNIGSKSVQWYQQKPGQAPVLVVYDDTVRPSGIPERFSGSNSGS
TATLTISRVEAGDEADYYCQVWDSSTDHLMFGGGTKLTVL
413 158
QVQFVQSGAEVKKPGASVKISCKASGYI FTSFGIHWVRQAPGQRLEWMGWINIGNGNTNYPQKFQGRV
TISRDTSASTAYMELSSLTFEDTAVYYCARDSDPTYGYFFPKYFYAMDVWGQGTTVTVSS
414 158
EIVLTQSPGTLSLSPGETATLSCRASQSVSSKYLAWYQQRPGQAPRLLIYGASSRATGIPDRFSSSAS
RTDFTLTISGLEPEDFAVYYCQQYGSLPQTFGQGSKLEIR
415 159
QVRLVESGGGVVQPGRSLRLSCAASGFSFTSYSVHWVRQAPGKGLEWVAVISYDGTNKYYADSVKGRF
TISRDSSKNTLYVQMSSLRAEDTAVYYCARVAYYYGSGSYYSPHFYYYGMDVWGQGTTVTVSS
416 159
QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKFMIYDVSKRPSGVPDRFSGSK
SGNTASLTISGLQAEDEADYYCCSYAGSYTWVFGGGTKLTVL
417 160
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWDDDKRYSPSLKSR
LTITKDTSKNQVVLTLTNMDPVDTATYYCAHRGPVAGHFGFWGQGTLVTVSS
418 160
EIVLTQSPGTLSLSPGERATLSCRASQSVSSRYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSASGS
GTDFTLTISRLEPEDFAVYYCQQYGNSRFTFGPGTKVDIK
419 161
EVHLVESGGGLVQPGGSLRLSCAASGFTFSNYWMHWVRQTPGKGLEGVANIKQDGSEEYYVDSVRGRF
TISRDNPHNSLYLQMNSLRAEDTAVYYCARVGPTGWRAGPFDSWGQGTLVTVSS
420 161
EVVLTQSPATLSLSPGERATLSCGASQSISNYLAWYQQKPGQSPRLLIYDASNRATGIPARFSGSGSG
TDFI LTISSLEPEDFAVYYCQQRSDWPPTFGGGTKVEIK
421 162
QVQLVQSGAEVMQVGASVKVSCKASAYKSTTYGIIWARQAPGQGLEFMGWVTPHNGVTKYEQKFQDRI
TITTDTSTGTAYMEMRSLRFDDTAIYYCARFVDSDDYRGWLDPWGRGTLVTVSS
422 162
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSG
TEFTLTISSLQPDDFATYYCQQYNSYPLTFGGGTKVEIK
423 163
EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYSMNWVRQAPGKGLEWVSSISGGSTYIYYADSLKGRF
TISRDNAKNSLYLQMNSLSAEDTAVYYCAKPLAAAGLLALDFWGQGTQVTVSS
424 163
AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQDYNYPRTFGQGTKLEIK
425 164
QVQLVQSGAEVMQVGASVKVSCKASAYKSTTYGIIWARQAPGQGLEFMGWVTPHNGVTKYEQKFQDRI
TITTDTSTGTAYMEMRSLRFDDTAIYYCARFVDSDDYRGWLDPWGRGTLVTVSS
426 164
EIVLTQSPGTLSLSPGERTTLSCRASQTVSNNYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDSAVYYCQQYAGSLPTFGGGTKVEIK
427 165
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGPEWMGRIIPIRAIANYAQKFQGRV
TITADKSTSTAYMELSSLRSEDTAVYYCARDYCTNGVCYAGQVLSFDIWGQGTMVTVSS
428 165
EIVMTQSPATLSVSPGERATLSCRASQSVGNSLAWYQQKPGQPPRLLIYDASTRATGIPASFSGIGSG
TEFTLTISSLQPEDFAAYHCQQYYNWPLTFGGGTKVEIK
429 166
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWDDDKRYSPSLKSR
LTITKDTSKNQVVLTLTNMDPVDTATYYCAHRGPVAGHFGFWGQGTLVTVSS
430 166
QSALTQPASVSASPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKVMIYEVSNRPSGVSNRFSGSK
SGNTASLTISGLQAEDEAHYYCSSYTSDYTWVFGGGTKLTVL
431 167
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWDDDKRYSPSLKSR
LTITKDTSKNQVVLTLTNMDPVDTATYYCAHRGPVAGHFGFWGQGTLVTVSS
432 167
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSG
TDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK
433 168
EVQLVDSGGGLIQPGGSLRLSCAASGFTFSNYGMSWVRQAPGKGLEWVSAISGSAGSTYYADSVKGRF
IISRDNSKNTLHLQMNSLRADDTAVYYCARSVGTTHYYMDVWGKGTTVTVSS
434 168
DIQMTQSPSSLSASVGDRVTITCRASQSITTYLNWYQHKPGKAPKLLIYAASTLQSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCQQSFITPAWTFGQGTKLEIK
435 169
EVQLVDSGGGLIQPGGSLRLSCAASGFTFSNYGMSWVRQAPGKGLEWVSAISGSAGSTYYADSVKGRF
IISRDNSKNTLHLQMNSLRADDTAVYYCARSVGTTHYYMDVWGKGTTVTVSS
436 169
SYELTQPPSVSVSPGQTARITCSGDALSKQYAYWYQKKPGQAPELVIYQDSERPSGIPERFSGSSSGT
TVTLTISGVQAEDEADYYCQSTDSSGTFGVFGGGTRLTVL
437 170
EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYSMNWVRQAPGKGLEWVSSISGGSTYIYYADSLKGRF
TISRDNAKNSLYLQMNSLSAEDTAVYYCAKPLAAAGLLALDFWGQGTQVTVSS
438 170
EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIAARFSGSGSG
TEFTLTISSLQSEDVAVYYCQQYNNWPVITFGPGTKVDIR
439 171
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGPEWMGRIIPIRAIANYAQKFQGRV
TITADKSTSTAYMELSSLRSEDTAVYYCARDYCTNGVCYAGQVLSFDIWGQGTMVTVSS
440 171
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSG
TEFI LTISTLQPDDFATYYCQQYNSYYTFGQGTKLEIK
441 172
QVQLVQSGAEVMQVGASVKVSCKASAYKSTTYGIIWARQAPGQGLEFMGWVTPHNGVTKYEQKFQDRI
TITTDTSTGTAYMEMRSLRFDDTAIYYCARFVDSDDYRGWLDPWGRGTLVTVSS
442 172
EIVLTQSPGTLSLSPGERAALSCRASQSLSSTYLAWYQQKPGQAPRLLIYAASSRATGIPDRFSGSGS
GTDFTLTIRRLEPEDFAVYYCQHFGTFGQGTTVEIK
443 173
QVQLVESGGSVVQPGRSLRLSCVASGFTFSKYAMHWVRQAPGKGLEWVAVVTYDGGAKYYADSVKGRF
TISRDNSENTLYLQMNSLRPEDTAVYFCAREWNYDSSPTYDFWGQGTLVTVSS
444 173
DIQMTQSPSSLSASVGDRVTITCRASQGISNSLAWYQQKPGRVPKLLIHSASTLQSGVPSRFSGSGSG
TDFTLTISSLQPEDVATYYCQKYNSAPFTFGPGTKVDIK
445 174
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWDDDKRYSPSLKSR
LTITKDTSKNQVVLTLTNMDPVDTATYYCAHRGPVAGHFGFWGQGTLVTVSS
446 174
ETVVTQSPATLSVPLGEGATLSCRVSQGVLTNVAWYQHRPGQAPRLLIYGASTRATGVPARFSGSGSG
TEFTLAISSLESEDVAVYYCHQYSKWPPGAFGQGTKVEIK
447 175
EVQLMQSGAQMKKPGESLKISCQGSGYNFPNSWIAWVRQMPGKGLEYMGIIYASNSDTRYSPSFQGQV
SISVDKSISTAYLQWSSLKASDTAMYYCARRADYAFDHWGQGTLVTVSS
448 175
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPYTFGQGTKLEIK
449 176
EVQLMQSGAQMKKPGESLKISCQGSGYNFPNSWIAWVRQMPGKGLEYMGIIYASNSDTRYSPSFQGQV
SISVDKSISTAYLQWSSLKASDTAMYYCARRADYAFDHWGQGTLVTVSS
450 176
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCQQSYSTPQFTFGGGTKVEIK
451 177
QVQLEDLGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGPEWMGRIIPIRAIANYAQKFQGRV
TITADKSTSTAYMELSSLRSEDTAVYYCARDYCTNGVCYAGQVLSFDIWGQGTMVTVSS
452 177
DIVMTQSPDSLAVSLGERATINCKSSQSI LYSSNNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRF
SGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPPTFGPGTKVDIK
453 178
QLQLQESGPGLVKPSETLSLTCTVSRGSISSSAYYWGWVRQPPGKGLEWIGSINYNGNTYYTSSLKSR
LTISVDTSRNQFSLKLSSVTAADTAVYYCARIIISGSNWFDPWGQGTLVTVSS
454 178
EIVLTQSPGTLSLSPGERAALSCRASQSLSSTYLAWYQQKPGQAPRLLIYAASSRATGIPDRFSGSGS
GTDFTLTIRRLEPEDFAVYYCQHFGTFGQGTTVEIK
455 179
QLQLQESGPGLVKPSETLSLTCTVSRGSISSSAYYWGWVRQPPGKGLEWIGSINYNGNTYYTSSLKSR
LTISVDTSRNQFSLKLSSVTAADTAVYYCARIIISGSNWFDPWGQGTLVTVSS
456 179
DIVLTQSPGTLSLSPGESATLSCRASQSVNNDYIAWYQQKPGQAPRLLIYGASSRASGIPDRFDGSGS
GTDFTLTIRRLEPDDFAVYYCHQYITLPLTFGGGSKVEIR
457 180
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPGKGLEWVSSISGSGDRIYGVDSLKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARRPLGSRFDLWGRGTLVTVSS
458 180
EIVMTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGTFDQGTKVEIK
459 181
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWDDDKRYSPSLKSR
LTITKDTSKNQVVLTLTNMDPVDTATYYCAHRGPVAGHFGFWGQGTLVTVSS
460 181
AIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQHKPGKAPKLLIYKASTLESGVPSRFSGSGSG
TEFTLTINSLQPDDFATYYCQQYNSPLTFGGGTKVEIK
461 182
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGPEWMGRIIPIRAIANYAQKFQGRV
TITADKSTSTAYMELSSLRSEDTAVYYCARDYCTNGVCYAGQVLSFDIWGQGTMVTVSS
462 182
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSG
TDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK
463 183
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGPEWMGRIIPIRAIANYAQKFQGRV
TITADKSTSTAYMELSSLRSEDTAVYYCARDYCTNGVCYAGQVLSFDIWGQGTMVTVSS
464 183
DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFQQRPGQSPRRLIYKVSNRDSGVPDRFS
GSGSGTDFTLKISRVEAEDVGVYYCMQGTHWPPRYTFGQGTKLEIK
465 184
QVQLQESGPGLVRPSETLSLTCTLSGGFISGSSYFWGFIRQPPGKGLEWIGSI FHNGTTKFNPSLKSR
VTISVEKSKNQFSLMLKSVTAADTAVYYCARHSPSMLRGVTIVGPHMDVWGKGTTVTAS
466 184
DIQMTQSPSAMSASVGDRVTITCRATQGFSNYLAWFQQRPGKAPKRLIYATSTLHSGVPSRFSGSGSG
TEFNLTISSLQPEDFATYYCLQHGRYPATFGQGTKLEIK
467 185
QVQLVESGGGVVQPGRSLRLSCEGSGFI FSDYTMGWVRQAPGKGLEWVALISHDGSTKRSADSVEGRF
SISRDNSKNLVHLHMDSLRAEDTAVYFCVRDHFLRLIREIWDNWGQGTQVTVSS
468 185
DIQMTQSPSAMSASVGDRVTITCRATQGFSNYLAWFQQRPGKAPKRLIYATSTLHSGVPSRFSGSGSG
TEFNLTISSLQPEDFATYYCLQHGRYPATFGQGTKLEIK
469 186
QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMTWIRQAPGKGLVWVSTISTSSSYTNSADSVKGRF
TMSRDDAENSLYLQMNNLRADDTAVYYCARAYTAMAPFDLWGQGTLVTVSS
470 186
EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSG
TEFTLTISSLQSEDFAVYYCQQYNNWPPWTFGQGTKVEIK
471 187
EVQLMQSGAQIKKPGESLKISCQGSGYNFPNSWIAWVRQMPGKGLEYMGIIYASNSDTRYSPSFQGQV
SISVDKSISTAYLQWSSLKASDTAMYYCARRADYAFDHWGQGTLVTVSS
472 187
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSG
TEFTLTISSLQPDDFATYYCQQYNSYSLTFGGGTKVEIK
473 188
EVQLVESGGGLVKPGGSLKLSCAASGFNLHSYTMNWVRQAPGKGLEWVSFITSDSRKTFYADSVRGRF
TISRDNAKNSLFLQMNSLRAEDTAVYYCARGVEWDTSTNWFASWGQGTLVTVSS
474 188
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCQQSYSTLLITFGPGTKVDIK
475 189
EVQLVESGGGLVKPGGSLKLSCAASGFNLHSYTMNWVRQAPGKGLEWVSFITSDSRKTFYADSVRGRF
TISRDNAKNSLFLQMNSLRAEDTAVYYCARGVEWDTSTNWFASWGQGTLVTVSS
476 189
EIVLTQSPATLSLSPGERAALSCRASQSVVNYLAWYQQRPGQAPRLLIYDASKRASGIPPRFSGNGSG
TDFTLTISSLEPEDFAVYYCQQRINWPLTFGGGTKVEIK
477 190
QVQLVQSGAEVMQVGASVKVSCKASAYKSTTYGIIWARQAPGQGLEFMGWVTPHNGVTKYEQKFQDKI
TITTDTSTGTAYMEMRSLRFDDTAIYYCARFVDSDDYRGWLDPWGRGTLVTVSS
478 190
DIQMTQSPSAMSASVGDRVTITCRATQGFSNYLAWFQQRPGKAPKRLIYATSTLHSGVPSRFSGSGSG
TEFNLTISSLQPEDFATYYCLQHGRYPATFGQGTKLEIK
479 191
QVQLVHGLDLEDLLLASVRVSCKASGYTFTNHPIDWVRQAPGQGLEWMGIINPSGGGVRFAQKFQGRV
TLTTDTSTSTVYMELSSLTSDDTAVYFCARGAGRDVYKSI LAWFDYWGQGTLVTVSS
480 191
QAALTQPASVSGSPGQSSAISCDVAGYSYVSWFQQHPGKAPKLMIYEVSKRPSGVSNRFSGSKSGNAA
SLTISGLQAEDEADYYCAAFTSRNTWVFGGGTRLTVL
481 192
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGPEWMGRIIPIRAIANYAQKFQGRV
TITADKSTSTAYMELSSLRSEDTAVYYCARDYCTNGVCYAGQVLSFDIWGQGTMVTVSS
482 192
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCQQSYSTLLITFGPGTKVDIK
483 193
QVQLVQSGAEVKRPGASVKISCKTSGYTFTNYAVHWLRQAPGQGLEWMGWINGGTGHTKYSRKFQGRV
TITRDTSASTAYMEVHSLRSEDTAVFYCAGSPTYYSWFDPWGQGTQVIVSS
484 193
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSG
TEFTLTISSLQPDDFATYYCQQYNSYSLTFGGGTKVEIK
485 194
CVQLVQSGGGLIQPGGSLRLSCAASGFSFSSYWMHWVRQAPGKGLVWVSRIYRDGSGPTYADSVKGRF
TI FRDSAKNTLYLQMNSLRAEDTAVYYCLRGNSGNGNFDLWGPGTLVTVSS
486 194
QAALTQPASVSGSPGQSSAISCDVAGYSYVSWFQQHPGKAPKLMIYEVSKRPSGVSNRFSGSKSGNAA
SLTISGLQAEDEADYYCAAFTSRNTWVFGGGTRLTVL
487 195
EVQLVESGGGLVQPGGSLRLSCAASGFSFNYDWMHWVRQAPGEGPVWVSCINGDGSTIRYGESVKGRF
TISRDNAKNTLYLQMNSLRLEDTAVYFCVRGTGYI LSYWGPGTVVTVSS
488 195
DIVLTQSPGTLSLSPGESATLSCRASQSVNNDYIAWYQQKPGQAPRLLIYGASSRASGIPDRFDGSGS
GTDFTLTIRRLEPDDFAVYYCHQYITLPLTFGGGSKVEIR
489 196
QVQLVQSGAEVMQVGASVKVSCKASAYKSTTYGIIWARQAPGQGLEFMGWVTPHNGVTKYEQKFQDRI
TITTDTSTGTAYMEMRSLRFDDTAIYYCARFVDSDDYRGWLDPWGRGTLVTVSS
490 196
DIQLTQSPSFLSASVGDRVTITCRASQGISNYLAWYQHRPGKAPKLLI FPASTLQSGVPSRFSGSGSG
TAFTLTISSLQPEDFATYYCQQLDTYSFGGGTKVEIK
491 197
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRF
TISRDNAKNSLYLQMNSLRAEDTAVYYCAEGSGSSSLQSYYWGQGTLVTVSS
492 197
DIVLTQSPGTLSLSPGESATLSCRASQSVNNDYIAWYQQKPGQAPRLLIYGASSRASGIPDRFDGSGS
GTDFTLTIRRLEPDDFAVYYCHQYITLPLTFGGGSKVEIR
493 198
QVQLVQSGAEVREPGSSVKVSCKASGDTLSNSAISWVRQAPGQGLEWMGRIIPMFGMASYSQKFQGRI
TISADKSTRTVYMELSSLTSEDTAVYYCARGGGTWAPFDPWGQGTQLTVSS
494 198
DIQLTQSPSFLSASVGDRVTITCRASQGISNYLAWYQHRPGKAPKLLI FPASTLQSGVPSRFSGSGSG
TAFTLTISSLQPEDFATYYCQQLDTYSFGGGTKVEIK
495 199
QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPSLKSR
VTISVDTSKNQFSLKLSSVTAADTAVYYCARKPSIAVAVRWGRSKINNWFDPWGQGTLVTVSS
496 199
DIQMTQSPSSLSASVGDRVTITCRASQGISNSLAWYQQKPGRVPKLLIHSASTLQSGVPSRFSGSGSG
TDFTLTISSLQPEDVATYYCQKYNSAPFTFGPGTKVDIK
497 200
EVQLVESGGGLVQPGGSLRLSCAASGFSFNYDWMHWVRQAPGEGPVWVSCINGDGSTIRYGESVKGRF
TISRDNAKNTLYLQMNSLRLEDTAVYFCVRGAGYI LSYWGPGTVVTVSS
498 200
QAVLTQPASVSGSPGQSSAISCDVAGYSYVSWFQQHPGKAPKLMIYEVSKRPSGVSNRFSGSKSGNAA
SLTISGLQAEDEADYYCAAFTSRNTWVFGGGTRLTVL
499 201
EVQLVESGGGLVKPGGSLKLSCAASGFNLHSYTMNWVRQAPGKGLEWVSFITSDSRKTFYADSVRGRF
TISRDNAKNSLFLQMNSLRAEDTAVYYCARGVEWDTSTNWFASWGQGTLVTVSS
500 201
AIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQHKPGKAPKLLIYKASTLESGVPSRFSGSGSG
TEFTLTINSLQPDDFATYYCQQYNSPLTFGGGTKVEIK
501 202
EVQLVQSGAEVKKSGESLKISCKGSGYSFSSYWIAWVRHMPGKGLEWMGIIYPGNSETKYSPSFQGQI
TMSVDKSISIAYLQWSSLKASDTAIYYCARRGYSISWGRVWMDVWGQGTTVTVSS
502 202
SYELTQPPSVSVAPGKTARITCGGNNIGSKSVHWYQQKPGQAPVLVIYDDSDRPSGIPERFSGSNSGN
TATLTISRVEAGDEADYYCQVWDSSSDHHAVFGGGTQLTVL
503 203
QVQLVQSGAEVKKPGSSVTVSCKASGGTFSSYGLSWVRQAPGQGPEWMGGIIPI LGKPTYAPKFQGRV
TITADESTSTAYLELSSLRSEDTATYYCARGGDYTGSYYDYYYYYMDAWGKGTTVTVSS
504 203
EIVLTQSPDTLSLSPGERATLSCRASQSVSNNRRLAWYQRKPGQAPRLLIYGASVRATGIPDRFSGSE
SGTDFTLTISRLEPEDFGVYYCQQYGNSPPTFGQGTKVELK
505 204
QVQLVESGGGVVQPGRSLRLSCAASGFTFRSYTMHWVRQAPGKGLEWVAVISYDGSYKYYADSVKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARDVI EYSGSSEYYGMDVWGQGTTVTVSS
506 204
DIQMTQSPSSLSASVGDRVTITCRASRSISNYLNWYQQKPGKVPKLLIYTASSLQSGVPSRFSGGGSG
TDFTLTISNLQPEDFATYYCQQSYSTLTFGGGTKVEIK
507 205
QVQLQQKGAALLKPSETLSLTCGVSGGTFSDYHWTWVRQPPGKGLEWIGKINHGGSTNYNPTLKSRVS
ISIDTSKSQFSLKMTSLTAADAAVYFCARLREGRALRLTPQPRYSYYHMDVWGKGTTVTVSS
508 205
DIQMTQSPSSLSASVGDRVTITCRASRSISNYLNWYQQKPGKVPKLLIYTASSLQSGVPSRFSGGGSG
TDFTLTISNLQPEDFATYYCQQSYSTLTFGGGTKVEIK
509 206
EVQLLESGGGLGQPGGSLRLSCAASGFTFSDYAMSWVRQAPGKGLEWVSTIDTSGRRTYYADSVKSRF
AISRDNSKDTLYLQVNTLRAEDTAIYYCAKDLAEEESLGFCDGNNCPDAFDIWGQRTRVTVSS
510 206
EIVLTQSPDTLSLSPGERATLSCRASQSVSNNRRLAWYQRKPGQAPRLLIYGASVRATGIPDRFSGSE
SGTDFTLTISRLEPEDFGVYYCQQYGNSPPTFGQGTKVELK
511 207
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRF
TISRDNAKNSLYLQMNSLRAEDTAVYYCARVLRLGELSFRNWGQGTLVTVSS
512 207
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPPYTFGQGTKLEIK
513 208
EVQLVESGGGLVQPGGSLKLSCAASGFTFSGSAIHWVRQASGKGLEWVGRIRSKANSYATAYAASVKD
RFTISRDDSKNTAYLQMNSLKSEDTAVYYCTRHNVDTALEWGQGTLVTVSS
514 208
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCSSYTSSSTLGVFGGGTKLTVL
515 209
QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYYADSVKGRF
TISRDNAKNSLYLQMNSLRAEDTAVYYCARVLRVRYSLFYYFDYWGQGTLVTVSS
516 209
SYELTQPPSVSVAPGKTARITCGGNNIGSKSVHWYQQKPGQAPVLVIYDDSDRPSGIPERFSGSNSGN
TATLTISRVEAGDEADYYCQVWDSSSDHHAVFGGGTQLTVL
517 210
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRF
TISRDNAKNSLYLQMNSLRAEDTAVYYCARPQSQLDRSGSSYFVAFDIWGQGTMVTVSS
518 210
QSVLTQPRSVSGSPGQSVTISCSGTSSDVGGFDYVSWYQQHPGKAPKLIIYGVTERPSGVPDRFSGSK
SANTASLTISGLQADDEAAYYCCSYAGTYI LLFGGGTKLTVL
519 211
QLQLQESGPGLVKSSEPLFLTCTVSGASISSSNYYWGWIRQPPGKGLEWIGSIYYSETTYYNPSLESR
VTISVDTSKHQFSLIVTSMTAADTAVYYCAGLRRGGNWFDPWGQGNPSHRLL
520 211
GIVMTQSPATLSVSPGERATLSCRASQSVSSSYLAWYQQKPGQPPRLLIYGASTRATGIPARFSGSGS
GTEFTLTISSLQSEDFAVYYCQQYSNWPLTFGGGTKVEIK
521 212
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRF
TISRDNAKNSLYLQMNSLRAEDTAVYYCARVLRLGELSFRNWGQGTLVTVSS
522 212
QSALTQPPSASGSPGQSVTISCTGTSRDVGGYDFVSWYQQHPGKAPKLMIYEVTKRPSGVPDRFSGSK
SGNRASLTVSGLQAEDEADYYCSSYAGNNI LFGGGTKLTVL
523 213
QVQLVESGGGVVQPGRSLRLSCAASGFTLRNYAMHWVRQAPGKGLEWVAVLSYDGNNKKYADSVKGRF
TISRDISNNTLYLHMDSLRAEDRAVYYCARDRTPYSSGWYVGYWGQGTLVTVSS
524 213
QSALTQPPSASGSPGQSVTISCTGTSRDVGGYDFVSWYQQHPGKAPKLMIYEVTKRPSGVPDRFSGSK
SGNRASLTVSGLQAEDEADYYCSSYAGNNI LFGGGTKLTVL
525 214
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRF
TISRDNAKNSLYLQMNSLRAEDTAVYYCARVLRLGEVSFRNWGQGTLVTVSS
526 214
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPPYTFGQGTKLEIK
527 215
QVQLVESGGGVVQPGRSLRLSCAASGFTFRSYTMHWVRQAPGKGLEWVAVISYDGSYKYYADSVKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARDVI EYSGSSEYYGMDVWGQGTTVTVSS
528 215
DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRFSGSGSG
TDFTLTISSLQPEDVATYYCQKYNSAPPWTFGQGTKVEIK
529 216
EVQLVESGGDLVQPGGSLRLSCAASGFTFTTYWMSWVRQTPGKGLEWLANIKQDGSEKYYVDSVKGRF
TISRDNAKNSVYLQMSSLRDEDTAVYYCARQGVVISSATNWFDPWGQGTLVTVSS
530 216
QSALTQPASVSGSPGQSITISCAGTRNDVGAYNYVSWHQQHPGQTPKLLIYDVDDRPSGVSNRFSGSK
SGNTASLTISRLQAEDEADYYCSSYTTSGTYVFGTGTKVTVV
531 217
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARGQSIAARPSWSDYYYMDVWGKGTTVTVSS
532 217
SYELTQPPSVSVAPGKTARITCGGDNIGSKSVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGN
TATLTISRVEAGDEADFYCQVWDGSSDHVVFGGGTKLTVL
533 218
QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSESVAWNWIRQSPSRGLEWLGRTYYRSRWYSDYAVSVK
SRITINPDTSKNQFSLQVSSMTPEDTAVYYCARVFSSSGHFDYWGQGTLVTVSS
534 218
EIVLTQSPDTLSLSPGERATLSCRASQSVSNNRRLAWYQRKPGQAPRLLIYGASVRATGIPDRFSGSE
SGTDFTLTISRLEPEDFGVYYCQQYGNSPPTFGQGTKVELK
535 219
EVQLVESGGGLVQPGGSLRLSCAASGFTFSHYWMAWVRQAPGKGLEWVANIKEDGSTKQYVGSVKGRF
TISRDNGKNLVYLQMNSLRAEDTAVYYCAKESGFWSGHYSSDDKFQHWGQGTWVTVSS
536 219
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLGWYQHKPGQAPRLLIYDTSNRATGIPARFSGSGSG
TDFI LTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK
537 220
QVQLVQSGAEVKKPGSSVTVSCKASGGTFSSYGLSWVRQAPGQGPEWMGGIIPI LGKPTYAPKFQGRV
TITADESTSTAYLELSSLRSEDTATYYCARGGDYTGSYYDYYYYYMDVWGKGTTVTVSS
538 220
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCSSYTSSSTLGVFGGGTKLTVL
539 221
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRF
TISRDNAKNSLYLQMNSLRAEDTAVYYCARVLRLGELSFRNWGQGTLVTVSS
540 221
GIVMTQSPATLSVSPGERATLSCRASQSVSSSYLAWYQQKPGQPPRLLIYGASTRATGIPARFSGSGS
GTEFTLTISSLQSEDFAVYYCQQYSNWPLTFGGGTKVEIK
541 222
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRF
TISRDNAKNSLYLQMNSLRAEDTAVYYCARVLRLGELSFRNWGQGTLVTVSS
542 222
QSVLTQPRSVSGSPGQSVTISCSGTSSDVGGFDYVSWYQQHPGKAPKLIIYGVTERPSGVPDRFSGSK
SANTASLTISGLQADDEAAYYCCSYAGTYI LLFGGGTKLTVL
543 223
EEQLVESGGGLVQPGGSLRLSCAASGFNFSSFWMHWVRQAPGKGLVWVSRIDSAGATTTYADSVKGRF
TISRDNANNTLYLQMSSLRAEDTAVYYCARLSSAPWSGFYVWHANWFDPWGQGTLVTVSS
544 223
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCSSYTSSSTLGVFGGGTKLTVL
545 224
EVHLVESGGGLVKPGESLRLSCEASGFTFTNAWMSWVRQAPGKGLEWIGRIKGESEGGTADYAAPVKG
RFSMSRDNSKNIVYLQMNSLKTEDTATYYCVTELGTALWVIDYFDNWGQGTLVTVSS
546 224
QSVLTQPPSASGSPGQSVTISCTGTSRDVGGYDFVSWYQQHPGKAPKLMIYEVTKRPSGVPDRFSGSK
SGNRASLTVSGLQAEDEADYYCSSYAGNNI LFGGGTKLTVL
547 225
EVQLLESGGGVVQPGGSVRLSCAASGFTFISYAMSWVRQAPGKGLEWVSAVSVSGGTTYYADSVKGRF
TISRDNSKKTLYLQMNSLRAEDTAVYYCAKEGVEMTRSFGYYFDHWGRGTLVTVSS
548 225
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLGWYQHKPGQAPRLLIYDTSNRATGIPARFSGSGSG
TDFI LTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK
549 226
EEQLVESGGGLVQPGGSLRLSCAASGFNFSSFWMHWVRQAPGKGLVWVSRIDSAGATTTYADSVKGRF
TISRDNANNTLYLQMSSLRAEDTAVYYCARLSSAPWSGFYVWHANWFDPWGQGTLVTVSS
550 226
SYELTQPPSVSVAPGKTARITCGGDNIGSKSVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGN
TATLTISRVEAGDEADFYCQVWDGSSDHVVFGGGTKLTVL
551 227
EVQLVESGGALVQPGGSLRLSCAASGSIVNNNYMNWVRQAPGKGLEWVSVIYKGGNTYYADSVKGRFT
ISRDNSKNMVYLQMNRLRAEDTAVYYCARALLGGTPNGPTNAWYWFHPWGLGTLVTVSS
552 1T1
DTQMTQSPSTLSASVGDRVTITCRASQSISTWLAWYQQKPGKAPKLLIYKASSVESGVPSRFSGSGSG
TEFTLTISSLQPDDLGTYYCQQYSTYSTFGQGTKVDIK
553 228
QVQLQQSGPGLVKPSQTLSLTCTISGDTVSSNSASWNWIRQSPSRGLEWLGRTKYRSKWYYDYAVSVK
SRISINPDTSKNQFSLQLNSVTPEDTAVYYCARGLDIPPDGIVGFDFWGQGTLVTVSS
554 228
DTQMTQSPSTLSASVGDRVTITCRASQSISTWLAWYQQKPGKAPKLLIYKASSVESGVPSRFSGSGSG
TEFTLTISSLQPDDLGTYYCQQYSTYSTFGQGTKVDIK
555 229
QLQLQESGPGLVKSSEPLFLTCTVSGASISSSNYYWGWIRQPPGKGLEWIGSIYYSETTYYNPSLESR
VTISVDTSKHQFSLIVTSMTAADTAVYYCAGLRRGGNWFDPWGQGTLVTVSS
556 229
DIQMTQSPSTLSASVGDRVSITCRASQSISTWLAWYQQKPGKAPKLLIYKASSLQSGVPSRFSGSGSG
TVFTLTISSLQPDDFATYYCQQYNSYSRTFGQGTKVEIK
557 230
QLQLVESGGGVVQTGRSLRLSCLASGFTLSGFAMHWVRQTPHKGLEWVAVISSDGGDIYYADSVKGRF
TISRDNFKNTI FLQMNNLRGDDTAVYFCVRPQSQLDRSGSSYFVAFDIWGQGTMVTVSS
558 230
DIQMTQSPSSLSASVGDRVSLTCRSSQTIYNYLNWYQQQPGKAPKLLIYAASTLHRGVPSRFSGSGSG
THFTLSISSLQHEDFATYYCQQNYLTPPWTFGPGTRVEVN
559 231
EVQLVESGGGWTGPGGSLRLSCAASGFI FSDHYMDWVRQAPGKGLEWVGRSWRKTESATPDYAASVRG
RFTISRDDSQNSLYLQMDSLKTEDTAVYYCATSVGDTADFDYWGQGALVTVSS
560 231
QSVLTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCSSYTSSSTLGVFGGGTKLTVL
561 232
QIQLQESGPGLVKPSQTLSLTCTVSGGSLSSGDYYWSWIRQPPGKGLEWIGYIYYSGSTSHNPSLKSR
VSISVDTSKNQFSLKLSSVSAADTAVYYCARYYYATSGFYERPPGPRFNWFDPWGQGTLVTVSS
562 232
SYELTQPPSVSVAPGKTARITCGGDNIGSKSVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGN
TATLTISRVEAGDEADFYCQVWDGSSDHVVFGGGTKLTVL
563 233
EVQLVESGGDLVQPGGSLRLSCAASGFTFSNYWMHWVRPAPGKGLVVVARISGDGSDADYADSVRGRF
TISRDNAKNTLFLQMNSLRVEDTAVYYCVRDRDVRDCNNGVCHTAYFNYWGQGTLVTVSS
564 233
QSALTQPPSASGSPGQSVTISCTGSRSDIGGYNYVSWYQHHPGKGPKLMIYEVSRRPSGVPDRFSGSK
SGNTASLTVSGLQADDEANYYCSSYGGSTNVI FGGGTKLTVL
565 234
QVQLVESGGGLVKPGGSLRLPCAASGFTFSDYYMSWIRQAPGKGLEWFSYISSSGSTIYYADSVKGRF
TISRDNAKNSLYLQMNSLRAEDTAVYYCARVLRVRYSLFYYFDYWGQGTLVTVSS
566 234
QSALTQPPSASGSPGQSVTISCTGTSRDVGGYDFVSWYQQHPGKAPKLMIYEVTKRPSGVPDRFSGSK
SGNRASLTVSGLQAEDEADYYCSSYAGNNI LFGGGTKLTVL
567 235
QLQLQESGPGLVKPSETLSLTCTVSGGSIRSSSYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPSLKSR
VTISVDTSKNQFSLKLSSVTAADTAVYYCAYYDFWSGLVWGKGTTVTVSS
568 235
DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRFSGSGSG
TDFTLTISSLQPEDVATYYCQKYNSAPPWTFGQGTKVEIK
569 236
EVQLVESGGGLVQPGGSLRLSCAASGFI FSDHYMVWVRQSPGKGREWVGRSWRKTESATPDYAASVRG
RFTISRDDSQNSLYLQMDSLKTEDTAVYYCATSVGDTADFDYWGQGALVTVSS
570 236
SYELTQPPSVSVAPGKTARITCGGDNIGSKSVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGN
TATLTISRVEAGDEADFYCQVWDGSSDHVVFGGGTKLTVL
571 237
QIQLQESGPGLVKPSQTLSLTCTVSGGSLSSGDYYWSWIRQPPGKGLEWIGYIYYSGSTSHNPSLKSR
VSISVDTSKNQFSLKLSSVSAADTAVYYCARYYYATSGFYERPPGPRFNWFDPWGQGTLVTVSS
572 237
QSVVTQPPSASGTPGQSVTISCSGSTSNIASSDVYWYQHLPGAAPNLLIYKNNQRPSGVPDRFSGSKS
GTSASLAISGLRAEDEANYYCATWDDSLRGPI FGGGTKLSVI
573 238
QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSESVAWNWIRQSPSRGLEWLGRTYYRSRWYSDYAVSVK
SRITINPDTSKNQFSLQVSSMTPEDTAVYYCARVFSSSGHFDYWGQGTLVTVSS
574 238
QSVLTQPPSASGSPGQSVTISCTGSRSDIGGYNYVSWYQHHPGKGPKLMIYEVSRRPSGVPDRFSGSK
SGNTASLTVSGLQADDEANYYCSSYGGSTNVI FGGGTKLTVL
575 239
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDHYMDWVRQAPGKGLEWVGRTRNRAKSYTTEYAASVKG
RFTISRDDSKNSLYLQMNSLKTEDTAVYYCARARPLGGSGTNYGMDVWGQGTTVTVSS
576 239
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCSSYTSSSTLGVFGGGTKLTVL
577 240
EVQLVESGGDLVQPGGSLRLSCAASGFTFSNYWMHWVRPAPGKGLVVVARISGDGSDADYADSVRGRF
TISRDNAKNTLFLQMNSLRVEDTAVYYCVRDRDVRDCNNGVCHTAYFNYWGQGTLVTVSS
578 240
SYELTQPPSVSVAPGKTARITCGGDNIGSKSVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGN
TATLTISRVEAGDEADFYCQVWDGSSDHVVFGGGTKLTVL
579 241
QLQLVESGGGVVQTGRSLRLSCLASGFTLSGFAMHWVRQTPHKGLEWVAVISSDGGDIYYADSVKGRF
TISRDNFKNTI FLQMNNLRGDDTAVYFCVRPQSQLDRSGSSYFVAFDIWGQGTMVTVSS
580 241
DTQMTQSPSTLSASVGDRVTITCRASQSISTWLAWYQQKPGKAPKLLIYKASSVESGVPSRFSGSGSG
TEFTLTISSLQPDDLGTYYCQQYSTYSTFGQGTKVDIK
581 242
QIQLQESGPGLVKPSQTLSLTCTVSGGSLSSGDYYWSWIRQPPGKGLEWIGYIYYSGSTSHNPSLKSR
VSISVDTSKNQFSLKLSSVSAADTAVYYCARYYYATSGFYERPPGPRFNWFDPWGQGTLVTVSS
582 242
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCSSYTSSSTLGVFGGGTKLTVL
583 243
QLQLVESGGGVVQTGRSLRLSCLASGFTLSGFAMHWVRQTPHKGLEWVAVISSDGGDIYYADSVKGRF
TISRDNFKNTI FLQMNNLRGDDTAVYFCVRPQSQLDRSGSSYFVAFDIWGQGTMVTVSS
584 243
QSALTQPPSASGSPGQSVTISCTGTSRDVGGYDFVSWYQQHPGKAPKLMIYEVTKRPSGVPDRFSGSK
SGNRASLTVSGLQAEDEADYYCSSYAGNNI LFGGGTKLTVL
585 244
QLQLVESGGGVVQTGRSLRLSCLASGFTLSGFAMHWVRQTPHKGLEWVAVISSDGGDIYYADSVKGRF
TISRDNFKNTI FLQMNNLRGDDTAVYFCVRPQSQLDRSGSSYFVAFDIWGQGTMVTVSS
586 244
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCSSYTSSSTLGVFGGGTKLTVL
587 245
QVQLVQSGAEVMQVGASVKVSCKTSGYTFTSYYLHWMRQAPGQGLEWMGIINPSGGSTSYAQKFQGRV
TMTRDTSTSTVYMELSSLRSEDTAVYYCARGALTMVRAVEYFQHWGQGTLVTVSS
588 245
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCSSYTSSSTLGVFGGGTKLTVL
589 246
QLQLVESGGGVVQTGRSLRLSCLASGFTLSGFAMHWVRQTPHKGLEWVAVISSDGGDIYYADSVKGRF
TISRDNFKNTI FLQMNNLRGDDTAVYFCVRPQSQLDRSGSSYFVAFDIWGQGTMVTVSS
590 246
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLIIYDVSNRPSGVSDRFSGSK
SDNTASLTISGLQAEDEADYYCNSYTSTSTLVFGGGTKLTVL
591 247
EEKLLESGGGLVKPGGSLRLSCTASGFVFKNYVMSWVRRAPGRGLEWISGIRGGDQMTFYANSVKGRF
IISRDNVKNMVHLQMNDLRDDDTAIYYCTKVVVESLENWFDAWGQGTLVTVTS
592 247
QSVLTQPPSVSGALGQRVTISCTGTSSNIGARYDVYWYQQFSGRAPKLLIYGNMNRASGVPDRFSGSK
SGTSASLAITGVQPEDEADYFCQSFDTRLNMVLFGGGTKLTVL
593 248
QVQLVQSGAEVMQVGASVKLSCEASGYKFTSYTMHWVRQAPGQRVEWMGWISVGNGNTKYSQKFQGRV
TITRDTSANTAYMEVRSLRSEDTAVYYCAREGYGSGTYFDYWGQGTLVTVSS
594 248
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLIIYDVSNRPSGVSDRFSGSK
SDNTASLTISGLQAEDEADYYCNSYTSTSTLVFGGGTKLTVL
595 249
EEKLLESGGGLVKPGGSLRLSCTASGFVFKNYVMSWVRRAPGRGLEWISGIRGGDQMTFYANSVKGRF
IISRDNVKNMVHLQMNDLRDDDTAIYYCTKVVVESLENWFDAWGQGTLVTVTS
596 249
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLGWYQHKPGQAPRLLIYDTSNRATGIPARFSGSGSG
TDFI LTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK
597 250
QLQLHESGPRLLKPSETLSLTCTVSGGSISNSNFCWGWIRQPPGKGLEWIGSVFYGGTTYYNPSLKSR
VALSLDASENQFSLKVTSVTAADTAMYYCARTRGRLYDYVGWYYYMDVWGRGTTVTVSS
598 250
KIVLTQSPATLSLSPGERATLSCRASQSVSSYLGWYQHKPGQVPRLLIYDTSNRATGIPARFSGSGSG
TDFI LTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK
599 251
EVQLVESGGGLVQPGGSLRLSCAASGFI FSDHYMDWVRQAPGKGLEWVGRSWRKTESATPDYAASVRG
RFTISRDDSQNSLYLQMDSLKTEDTAVYYCATSVGDTADFDYWGQGALVTVSS
600 251
QSVLTQPRSASGTPGQRVTISCSGSRSNIGRNTVNWYQQLPGTAPKLLI FGNDQRPSGVPDRFSGSKS
GTSASLAISGLQSEDEADYYCAAWDDTLNGLYVFGTGTKVTVL
601 252
EVQLVESGGGLVQPGGSLRLSCAASGFI FSDHYMDWVRQAPGKGLEWVGRSWRKTESATPDYAASVRG
RFTISRDDSQNSLYLQMDSLKTEDTAVYYCATSVGDTTDFDYWGQGALVTVSS
602 252
KIVLTQSPGTLSVSPGERVTLSCRTSQSVSNNYLAWYQHKPGQAPRLLIYGASSGASDIPDRFSGGGS
GTDFTLTISRLEPEDFAVYYCQQYGTSPWTFGQGTKVEIK
603 253
EVQLVQSGAEVKKPGESLRISCKASGYSFANYWINWVRQMPGEGLEWLGRIDPSDSYTNYSPSFQGHV
TISTDTSISTVYLQWRSLKASDTAMYYCARPAAEVVPDSLVEDPFNVWGQGTMVTVSS
604 253
QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYSNNQRPSGVPDRFSGSKS
GTSASLAISGLQSEDEADYYCAAWDDSLNGPVFGGGTKLTVL
605 254
QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYHDYALSVK
SRITINPDTSKNQFSLQLNSVTPEDTAVYYCARAAWEGGGYQLVLYYSYYYGMDVWGQGTTVTVSS
606 254
QSVLTQPPSVSGALGQRVTISCTGTSSNIGARYDVYWYQQFSGRAPKLLIYGNMNRASGVPDRFSGSK
SGTSASLAITGVQPEDEADYFCQSFDTRLNMVLFGGGTKLTVL
607 255
EEKLLESGGGLVKPGGSLRLSCTASGFVFKNYVMSWVRRAPGRGLEWISGIRGGDQMTFYANSVKGRF
IISRDNVKNMVHLQMNDLRDDDTAIYYCTKVVVESLENWFDAWGQGTLVTVTS
608 255
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPPYTFGQGTKLEIK
609 256
EVQLVESGGGLVQPGGSLRLSCVASGFPFDNSAMHWVRQAPGKGLEWVSGINWNSVTMDYGDSVKGRF
TISRDYAKNSVYLQMNNLRI EDTALYYCAKADCSSTSCFMDVWGRGTTVTVSS
610 256
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLGWYQHKPGQAPRLLIYDTSNRATGIPARFSGSGSG
TDFI LTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK
611 257
QVQLVQSGAAVKKPGAAVKVSCKPSGYTFASHDINWVRQATGQGLEWMGWMNPKSGNTGYAQKFRGRL
TMTRNASTTTAYMEMTGLTSEDSAVYYCARGRVGKPQDYYYHLDVWGKGTTVTVSS
612 257
QSVLTQPPSVSGAPGQKVTISCTGGSSNIGADYDVHWYQHLPETAPKLLIYGNSNRPSGVPDRFSGSK
SGTSASLAITGLQAEDEADYYCQSYDSSLGGSYVFGTGTKVTVL
613 258
QVQLVESGGGLVKPGGSLRLSCAASGFI FSDYYMSWIRQAPGKGLEWVSYISGSGGTIHYADSVRGRF
TISRDNAKNSLYLQVNSLRAEDTAVYYCARELVPVAMRHYYFYGMDVWGQGTTVTVSS
614 258
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSK
SGTSASLAITGLQAEDEADYYCQSYDRSLSGPVVFGGGTKLTVL
615 259
EEKLLESGGGLVKPGGSLRLSCTASGFVFKNYVMSWVRRAPGRGLEWISGIRGGDQMTFYANSVKGRF
IISRDNVKNMVHLQMNDLRDDDTAIYYCTKVVVESLENWFDAWGQGTLVTVTS
616 259
QSALTQPRSVSGSPGQSVTISCTGTSSDVGSNNYVSWYQQHPGKAPKLMIYDVSKRPSGVPDRFSGSK
SDNTASLTISGLQAEDEADYYCCSYTGSRVVFGGGTKLTAL
617 260
EVQLVESGGDLVQPGGSLRLSCAASGFTFSNYWMHWVRPAPGKGLVVVARISGDGSDADYADSVRGRF
TISRDNAKNTLFLQMNSLRVEDTAVYYCVRDRDVRDCNNGVCHTAYFNYWGQGTLVTVSS
618 260
QSVLTQPPSVSGALGQRVTISCTGTSSNIGARYDVYWYQQFSGRAPKLLIYGNMNRASGVPDRFSGSK
SGTSASLAITGVQPEDEADYFCQSFDTRLNMVLFGGGTKLTVL
619 261
QIQLQESGPGLVKPSQTLSLTCTVSGGSLSSGDYYWSWIRQPPGKGLEWIGYIYYSGSTSHNPSLKSR
VSISVDTSKNQFSLKLSSVSAADTAVYYCARYYYATSGFYERPPGPRFNWFDPWGQGTLVTVSS
620 261
QSVLTQPPSVSGALGQRVTISCTGTSSNIGARYDVYWYQQFSGRAPKLLIYGNMNRASGVPDRFSGSK
SGTSASLAITGVQPEDEADYFCQSFDTRLNMVLFGGGTKLTVL
621 262
EVQLVESGGGLVQPGGSLRLSCAASGFI FSDHYMDWVRQAPGKGLEWVGRSWRKTESATPDYAASVRG
RFTISRDDSQNSLYLQMDSLKTEDTAVYYCATSVGDTADFDYWGQGALVTVSS
622 262
DIQMTQSPSSVSASIGDRVTITCRASQGINRWLPWYQQKPGKAPRLLIYAASSLQSGVPSRFSGSGSG
TDFTLTISSLQPEDFCNLLLSTGSDFPPHFRRRDQGGDQ
623 263
EVQLVESGGGLVQPGGSLRLSCVASGFPFDNSAMHWVRQAPGKGLEWVSGINWNSVTMDYGDSVKGRF
TISRDYAKNSVYLQMNNLRI EDTALYYCAKADCSSTSCFMDVWGRGTTVTVSS
624 263
QSVLTQPPSVSGALGQRVTISCTGTSSNIGARYDVYWYQQFSGRAPKLLIYGNMNRASGVPDRFSGSK
SGTSASLAITGVQPEDEADYFCQSFDTRLNMVLFGGGTKLTVL
625 264
EVQLVESGGGLVQPGGSLRLSCAASGFI FSDHYMDWVRQAPGKGLEWVGRSWRKTESATPDYAASVRG
RFTISRDDSQNSLYLQMDSLKTEDTAVYYCATSVGDTADFDYWGQGALVTVSS
626 264
EIVMTQSPATLSVSPGEKATLSCKASQSLSSDLAWYQQKRGQAPRLLIYGASTRASGIPARFSGSGSG
TEFTLTITSLQSEDFQVYYCQQYNNWPPTFGLGTKVEIN
627 265
EVQLVESGGGLVQPGGSLRLSCVASGFPFDNSAMHWVRQAPGKGLEWVSGINWNSVTMDYGDSVKGRF
TISRDYAKNSVYLQMNNLRI EDTALYYCAKADCSSTSCFMDVWGRGTTVTVSS
628 265
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLIIYDVSNRPSGVSDRFSGSK
SDNTASLTISGLQAEDEADYYCNSYTSTSTLVFGGGTKLTVL
629 266
EVQLVESGGGLVQPGGSLRLSCAASGFI FSDHYMDWVRQAPGKGLEWVGRSWRKTESATPDYAASVRG
RFTISRDDSQNSLYLQMDSLKTEDTAVYYCATSVGDTADFDYWGQGALVTVSS
630 266
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLIIYDVSNRPSGVSDRFSGSK
SDNTASLTISGLQAEDEADYYCNSYTSTSTLVFGGGTKLTVL
631 267
QLQLVESGGGVVQTGRSLRLSCLASGFTLSGFAMHWVRQTPHKGLEWVAVISSDGGDIYYADSVKGRF
TISRDNFKNTI FLQMNNLRGDDTAVYFCVRPQSQLDRSGSSYFVAFDIWGQGTMVTVSS
632 267
DIVMTQTPLSLSVTPGQPASISCKSSQSLLHSDGKTYLYWYLQKPGQPPQLLIYEVSNRFSGVPDRFS
GSGSGTDFTLKISRVEAEDVGVYYCMQTIQLPPYTFGQGTKLEIK
633 268
EVQLLESGGGLVQPGGSLRLSCAASGFRFSSYAMSWVRQAPGKGLEWVSAISGSGGNTYYADSVKGRF
TISRDNSKNTLYLQMSSLRVGDTAIYYCAKRDSAPYPDSFDYWGQGTLVTVSS
634 268
EIVLTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSESG
TELTLTISSLQSEDFAVYYCQYRGTFGQGTKLEIK
635 269
QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYYADSVKGRF
TISRDNAKNSLYLQMNSLRAEDTAVYYCARVLRVRYSLFYYFDYWGQGTLVTVTS
636 269
QSALTQPASVSGSPGQSITISCTGTSSDIGGYDYVSWYQQHPDTAPKLIIYDVYNRPSGVPDRFTASK
SDNTASLTISGLQAEDEADYFCSSYANVNTI LFGGGTKVTVL
637 270
EVQLVESGGGLVQPGGSLRLSCAASGFI FSDHYMDWVRQAPGKGLEWVGRSWRKTESATPDYAASVRG
RFTISRDDSQNSLYLQMDSLKTEDTAVYYCATSVGDTADFDYWGQGALVTVSS
638 270
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRFLIYGASSRATGIPDRFSGSGS GTDFTLTISRLEPEDFAVYYCQQYGSSPPYTFGQGTKLEIK
639 271
QVHLVESGGGVVQPGRSLRLSCAASGFSFSSYGLHWVRQAPGKGLEWVAFISYVGSNKYYADSVKGRF
TISRDNSKNTLYLQMNSLRTEDTAVYYCAREYTVGGI FGFWGQGTLVTVSS
640 271 EVVLTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGFPARFSGSGSG
TEFTLTISSLQSEDFAIYHCQQYNNWPLTFGGGTKVEIK
641 272 QVQLVQSGAAVKKPGAAVKVSCKPSGYTFASHDINWVRQATGQGLEWMGWMNPKSGNTGYAQKFRGRL
TMTRNASTTTAYMEMTGLTSEDSAVYYCARGRVGKPQDYYYHLDVWGKGTTVTVSS
642 272 EIVMTQSPATLSVSPGERVTLSCRASQSVGSNLAWYQQKPGQAPRLLIYGASSRAAGIPDRFRGTGSG
TEFTLTISNLQSEDFAVYYCQQYENWPPWTFGQGTKVEIK
643 273 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPI LGIANYAQKFQGRV
TITADKSTSTAYMELSSLRSEDTAVYYCARDAIVVVNYYYGMDVWGQGTTVTVSS
644 273
DIQMTQSPLLLLWLPGDRVTITCRASQSISTWLAWYQQKPGKAPKLLIYKASSVESGVPSRFSGSGSG
TEFTLTISSLQPDDLGTYYCQQYSTYSTFGQGTKVDIK
645 274
EEKLLESGGGLVKPGGSLRLSCTASGFVFKNYVMSWVRRAPGRGLEWISGIRGGDQMTFYANSVKGRF
IISRDNVKNMVHLQMNDLRDDDTAIYYCTKVVVESLKNWFDAWGQGTLVTVTS
646 274
QSVLTQPRSASGTPGQRVTISCSGSRSNIGRNTVNWYQQLPGTAPKLLI FGNDQRPSGVPDRFSGSKS
GTSASLAISGLQSEDEADYYCAAWDDTLNGLYVFGTGTKVTVL
647 275
EVQLVESGGGLVQPGGSLRLSCAASGFI FSDHYMDWVRQAPGKGLEWVGRSWRKTESATPDYAASVRG
RFTISRDDSQNSLYLQMDSLKTEDTAVYYCATSVGDTADFDYWGQGALVTVSS
648 275
EIVLTQSPGTLSLSPGERAI LSCRASQTVISGYLAWYQQKPGQTPRLLISGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPYTFGQGTKLEIK
649 276
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQV
TISADKSISTAYLQWSSLKASDTAMYYCARKDIYYYYMDVWGKGTTVTVSS
650 276 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSK
SGTSASLAITGLQAEDEADYYCQSYDSSLSGPVVFGGGTKLTVL
651 277 QVQLVQSGTEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPI LGIANYAQKFQGRV
TITADKSTSTAYMELSSLRSEDTAVYYCARDAIVVVNYYYGMDVWGQGTTVTVSS
652 277 QSVLTQPPSVSGALGQRVTISCTGTSSNIGARYDVYWYQQFSGRAPKLLIYGNMNRASGVPDRFSGSK
SGTSASLAITGVQPEDEADYFCQSFDTRLNMVLFGGGTKLTVL
653 278
EVQLVESGGGLVKPGGSLRLSCAASGLTFSNAWMNWVRQAPGKGLEWVGRIKSKADGGTTDYAVPVKD
RFTISRDDSKNTLFLQMNSLKTEDTAVYYCTTITGSTYSFRFSTYYYYYYYLDVWGKGTTVTVTS
654 278
SYELTQPPSVSVAPGKTARITCGGDNIGSKSVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGN
TATLTISRVEAGDEADFYCQVWDGSSDHVVFGGGTKLTVL
655 279
EVQLVESGGGLVQPGGSLRLSCVASGFPFDNSAMHWVRQAPGKGLEWVSGINWNSVTMDYGDSVKGRF
TISRDYAKNSVYLQMNNLRI EDTALYYCAKADCSSTSCFMDVWGRGTTVTVSS
656 279
EIVLTQSPGTLSLSPGERATLSCRASQSVSSIYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS GTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK
657 280
EEQLLESGGGLVKPGGSLSLSCTASGFVFRSYVMSWVRRAPGRGLEWISGIRGGDQMTFYANSVKGRF
IISRDNVKNMVHLQMNDLRDDDTAIYYCTKVIGESLENWFDAWGKGTLVTVTS
658 280 QSVLTQPPSVSGALGQRVTISCTGTSSNIGARYDVYWYQQFSGRAPKLLIYGNMNRASGVPDRFSGSK
SGTSASLAITGVQPEDEADYFCQSFDTRLNMVLFGGGTKLTVL
659 281 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPI LGIANYAQKFQGRV
TITADKSTSTAYMELSSLRSEDTAVYYCARDAIVVVNYYYGMDVWGQGTTVTVSS
660 281 DIVMTQTPLSLSVTPGQPASISCKSSQSLLHSDGKTYLYWYLQKPGQPPQLLIYEVSNRFSGVPDRFS
GSGSGTDFTLKISRVEAEDVGVYYCMQTIQLPPYTFGQGTKLEIK
661 282 EVQLVESGGGLVKPGGSLRLSCAASGLTFSNAWMNWVRQAPGKGLEWVGRIKSKADGGTTDYAVPVKD
RFTISRDDSKNTLFLQMNSLKTEDTAVYYCTTITGSTYSFRFSTYYYYYYLDAWGQGTLVTVTS
662 282
DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRFSGSGSG
TDFTLTISSLQPEDVATYYCQKYNSAPPWTFGQGTKVEIK
663 283 EEKLLESGGGLVKPGGSLRLSCTASGFVFKNYVMSWVRRAPGRGLEWISGIRGGDQMTFYANSVKGRF
IISRDNVKNMVHLQMNDLRDDDTAIYYCTKVVVESLENWFDAWGQGTLVTVLE
664 283 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPGYTFGQGTKLEIK
665 284 EEKLLESGGGLVKPGGSLRLSCTASGFVFKNYVMSWVRRAPGRGLEWISGIRGGDQMTFYANSVKGRF
IISRDNVKNMVHLQMNDLRDDDTAIYYCTKVVVESLENWFDAWGQGTLVTVTS
666 284 PSVLTQLRSASGPPGQRVTISWSGSRSHIGSNPVNWYQPLPGPAHKLLI FGNDQRPSGVPDRFSGSKS
GTSASLAISGLQSEDEADYYCAAWDDTLNGLYVFGTGI FFFKQ
667 285 QVQLVQSGAEVMQVGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGLINPNSGGTNYAQKFQGWV
TMTRDTSISTAYMELSRLRSDDTAVYYCARDGSGVVPAAISSYYYYGMDVWGQGTTVTVSS
668 285
EIVLTQSPGTLSLSPGERATLSCRASQSVRGTYLAWYQQKPGQAPRLVIYAASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPGTFGQGTKLEIK
669 286 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPI FGTANYAQKFQGRV
TITADESTSTAYMELSSLRSEDTAVYYCALVTAIPPYYFDYWGQGTLVTVSS
670 286 QSVLTQPPSASGTPGQTVTISCSGSSSNIGSNYVYWYQQVPGTAPQLLIYRNNQRPSGVPDRFSGSKS
GTSASLAISGLRSGDEADYYCAAWDDSLSGHVVFGGGTKVTVL
671 287
QVQLQQWGAGLLKPSETLSLTCGVYGGSFTGYYWSWIRQAPGKGLEWIGEINHNGRSTNYNPSLKSRV
TISVDTSNNQFSLKVRSVTAADTAVYYCARERDYNHYYYWHMDVWGKGTTVTVSS
672 287 EIVLTQSPGTLSLSPGERATLSCRASQSVRGTYLAWYQQKPGQAPRLVIYAASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPGTFGQGTKLEIK
673 288 QVQLVQSGAEVKKPGASVKLSCKASGYSFTTYTMSWVRQAPGRGLEWMGWINPANGHTEYMERFRGRV
TITRDTSASTAYMELSSLTSEDTTIYFCARIYCSGDHCYDYWGQGI LVTVSS
674 288
EIVLTQSPGTLSLSPGERATLSCRASQSVRGTYLAWYQQKPGQAPRLVIYAASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPGTFGQGTKLEIK
675 289
QVQLVQSGAEVKKPGASVKVSCTTSGFI FISHYMHWVRQAPGQGLEWMGIITPANTTKYSQRFQGRVT
MTSDASTSTVYMELSSLRSEDTAVYYCAREWGELDSSVFDYWGQGTLVTVSA
676 289
QSVLTQSPSASASLGASVKLTCTLSSGHTNYAIAWHQQQPDKGPRFLMRLNSDGSHIKGDGIPDRFSG
SSSGPERYLTISSLQSEDEADYYCQTWGTGTQVFGTGTKVTVL
677 290
QVQLVQSGAEVMQVGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNYAQKFQGWV
TMTRDTSISTAYMELSRLRSDDTAVYYCARDGSGVVPAAISSYYYYGMDVWGQGTTVTVSS
678 290
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCSSYTSSSNWVFGGGTKLTVL
679 291
QVQLVQSGAEVMQVGASVKVSCKASNYTFTSFGINWVRQAPGQGLEWMGWISPYNGNTNYAQDLQGRV
TMTTDTSTSTAYMELRSLRSDDTAVYYCARERDHNYSNFYYYYGMDVWGQGTTVTVSS
680 291
EIVLTQSPGTLSLSPGERATLSCRASQSVRGTYLAWYQQKPGQAPRLVIYAASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPGTFGQGTKLEIK
681 292
QVQLVQSGAEVMQVGASVKVSCTTSGFI FISHYMHWVRQAPGQGLGWMGIITPANTTKYSQRFQGRVT
MTSDASTSTVYMELSSLRSEDTAVYYCAREWGELDSSVFDYWGQGTLVTVSA
682 292
EIVLTQSPGTLSLSPGERATLSCRASQSVRGTYLAWYQQKPGQAPRLVIYAASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPGTFGQGTKLEIK
683 293
EVQLVESGGGLVKPGGSLRLSCAASI FTFSDYTMNWVRQAPGKGLEWVSSISSTGTYIYYAGSVRGRF
TISRDNAKKLLYLQMNGLRAEDTAVYYCTRELTTVTRFRYWFDPWGQGTQVTVSS
684 293
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGFDVHWYQQLPGTAPKLLIYDNSNRPSGVPDRFSGSK
SGTSASLAITGLQAEDEAHYYCQSYDSTLIGSVFGGGTKLTVL
685 294
EVQLVQSGAEVKKPGESLKISCKVSGYNFASYCIGWVRQMPGKGLEWMGII FPGDSDTRYSPSFQGQV
TFSADKSISTAYLQWSSLKASDTAMYYCARGRVLVRGVISEDYFDYWGHGTLVTVSS
686 294
QSVLTQSPSASASLGASVKLTCTLSSGHTNYAIAWHQQQPDKGPRFLMRLNSDGSHIKGDGIPDRFSG
SSSGPERYLTISSLQSEDEADYYCQTWGTGTQVFGTGTKVTVL
687 295
EVQLVQSGAEVKKPGESLKISCKGSGYSFPNYWIGWVRQMSGQGLEWMAIIYPGNSDTRYSPSLQDQV
TISADKSISTAYLQWSSLKASDTAMYFCARLSYFGSGTYYPFDYWGQGTLVTVSS
688 295
EIVLTQSPGTLSLSPGERVTLSCRTSQSVSGDYLAWYRQKPGQPPRLLVYRTSSRATGIPDRFSGSGS
RTDFTLSISGLEPEDFAVYYCQHYGSSHYTFGQGTKLEIK
689 296
QVQLVQSGAEVMQVGASVKVSCKAYGYTFSTHGISWVRQAPGQGLEWMGWISAYNGDTKFAQKVQGRV
TMTTDTSTSTAYMELRSLRSDDTAMYFCAREGADYGDRESMDAFDIWGRGTMVTVSS
690 296
QSVLTQPPSVSGAPGQRVAFSCTGSSSNIGAGFDVHWYQQLPGTAPKLLIYANSNRPSGVPDRFSGSK
SGTSASLAITGLQVEDEADYYCQSYDSSLSWVFGGGTKLTVL
691 297
EEKLLESGGGLVKPGGSLRLSCTASGFVFKNYVMSWVRRAPGRGLEWISGIRGGDQMTFYANSVKGRF
IISRDNVKNMVHLQMNDLRDDDTAIYYCTKVVVESLENWFDAWGQGTLVTVTS
692 297
EIVLTQSPGTLSLSPGERATLSCRASQSVRGTYLAWYQQKPGQAPRLVIYAASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPGTFGQGTKLEIK
693 298
QVQLVQSGAEVKKPRPSLKVSCKASGGTFTGYAISWVRHAPGQGLQWLGGIIPI FGTANYAQKFQGRV
TITADESTSTAYMELSSLRSEDTAVYYCALVTAIPPYYFDYWGQGTLVTVSS
694 298
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCSSYTSSSTLVFGGGTKLTVL
695 299
QVQLQESGPGLVKPSETLSLTCTVSGASVTSNNYYWSWVRQPPGKGLEWIGHISYRGITNYIPSLKSR
VTISADTSKNQFSLNLKSVIDADTAVYYCVREDLVSQSRYYYYYMDVWGKGTTVTVSS
696 299
EIVLTQSPATLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGTPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPYTFGQGTKLEIK
697 300
QVQLVQSGAEVMQVGASVKVSCKASGYTFTLYAMHWVRQAPGQRLEWLGWINAGNGDTKYSQKFQGRV
TITRDTPASTAYMELSSLRSEDTAIYYCARDKEGWNDPNYFDFWGQGTLVTVSS
698 300
QSALTQPASVSGSPGQSITISCTGTSSDVGGHNYVSWYQQYPGKAPKLMIYDVSNRPSGVSNRFSASK
SGNTASLTISGLQAEDEGDYYCSSYTSRSTLVFGGGTKLTVL
699 301
QVQLVQSGAEVMQVGASVKVSCKASGYTFTLYAMHWVRQAPGQRLEWLGWINAGNGDTKYSQKFQGRV
TITRDTPASTAYMELSSLRSEDTAIYYCARDKEGWNDPNYFDFWGQGTLVTVSS
700 301
QSVLTQPPSLSAAPGQKVTISCSGSSKIDYVSWYQQFPGTAPKLLIYDNSHRPSGIPDRFSGSKSGTS
ATLGITGLQTGDEADYYCGTWDSRLNVYVFGPGTKVTVL
701 302
EVQLVESGGDLVQPGGSLRLSCAASGFTFSNYWMHWVRPAPGKGLVVVARISGDGSDADYADSVRGRF
TISRDNAKNTLFLQMNSLRVEDTAVYYCVRDRDVRDCNNGVCHTAYFNYWGQGTLVTVSS
702 302
DIQVTQSPSTLSASVGDRVTITCRGSQRLTNWLAWYQQKPGKAPKLLIYKASI LHSGVPSRFSGSESG
TEFTLTISSVQPDDFATYYCQHYDTYWTFGQGTKVEIK
703 303
QVQLVESGGGVVQPGRSLRLSCAASGFTLRNYAMHWVRQAPGKGLEWVAVLSYDGNNKKYADSVKGRF
TISRDISNNTLYLHMDSLRAEDRAVYYCARDRTPYSSGWYVGYWGQGTLVTVSS
704 303
EIVLTQSPATLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGTPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPYTFGQGTKLEIK
705 304
QVQLVQSGAEVKKPGSSVTVSCKASGGTFSSYGLSWVRQAPGQGPEWMGGIIPI LGKPTYAPKFQGRV
TITADESTSTAYLELSSLRSEDTATYYCARGGDYTGSYYDYYYYYMDVWGKGTTVTVSS
706 304
QSALTQPASVSGSPGQSITISCTGTSSDVGGHNYVSWYQQYPGKAPKLMIYDVSNRPSGFSNRFSASK
SGNTASLTISGLQAEDEGDYYCSSYTSRSTLVFGGGTKLTVL
707 305
QVQLVQSGAEVMQVGASVKVSCKASGYTFINYGISWVRQAPGQGLEWMGWISTYNGNTDFAQKLQGRF
TMTTDTSASTAYMEVRSLRSDDTAVYYCARDRRLGTPASGWTADYSYSYMDVWGTGTTVTVSS
708 305
EIVLTQSPATLSLSLGERATLSCRASQSVRRYLAWFQQRPGQSPRLLIYDASNRATGIPARFSGSGSG
TDFTLTISSLEPEDFAIYYCQQRSHWPKYTFGQGTKLEIK
709 306
EVQLVESGGDLVQPGGSLRLSCAASGFSFSSFSMTWVRQAPGKGLEWVAYISGNGYIIYYTDSVKGRF
TISRDNARNSLYLQLNSLRAEDTAVYFCASWVDSRGYYYVDYFDNWGQGTLVTVSS
EIVLTQSPATLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGTPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPYTFGQGTKLEIK
711 307
EEKLLESGGGLVKPGGSLRLSCTASGFVFKNYVMSWVRRAPGRGLEWISGIRGGDQMTFYANSVKGRF
IISRDNVKNMVHLQMNDLRDDDTAIYYCTKVVVESLENWFDAWGQGTLVTVTS
712 307
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCSSYTSSSTLVFGGRTKLTVL
713 308
QVQLVQSGAEVKKPGSSVTVSCKASGGTFSSYGLSWVRQAPGQGPEWMGGIIPI LGKPTYAPKFQGRV
TITADESTSTAYLELSSLRSEDTATYYCARGGDYTGSYYDYYYYYMDVWGKGTTVTVSS
714 308
EIVLTQSPDTLSLSPGERATLSCRASQSVSNNRRLAWYQRKPGQAPRLLIYGASVRATGIPDRFSGSE
SGTDFTLTISRLEPEDFGVYYCQQYGNSPPTFGQGTKVELK
715 309
QVQLVESGGGVVQPGRSLRLSCAASGFTLRNYAMHWVRQAPGKGLEWVAVLSYDGNNKKYADSVKGRF
TISRDISNNTLYLHMDSLRAEDRAVYYCARDRTPYSSGWYVGYWGQGTLVTVSS
716 309
QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSKRPSGVPDRFSGSK
SGNTASLTISGLQAEDEADYYCCSYAGSYTFVVFGGGTKLTVL
717 310
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDHYMDWVRQAPGKWLEWVGRTRNRAKSYTTEYAASVKG
RFTISRDDSKNSLYLQMNSLKTEDTAVYYCARARPLGGSGTNYGMDVWGQGTTVTVSS
718 310
EIVLTQSPATLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGTPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPYTFGQGTKLEIK
719 311
EVHLVESGGGLVKPGESLRLSCEASGFTFTNAWMSWVRQAPGKGLEWIGRIKGESEGGTADYAAPVKG
RFSMSRDNSKNIVYLQMNSLKTEDTATYYCVTELGTALWVIDYFDNWGQGTLVTVSS
720 311
QSVLTQPPSLSAAPGQKVTISCSGSSKIDYVSWYQQFPGTAPKLLIYDNSHRPSGIPDRFSGSKSGTS
ATLGITGLQTGDEADYYCGTWDSRLNVYVFGPGTKVTVL
721 312
EVQLLESGGGLVQPGGSLRLSCAASGFTFNIYAINWVRQAPGKGLEWVSSISGSGDSAYYADSVKGRF
TISRDNSKNTVFLQMNSLTAEDTAVYYCAKQYCTNGVCYTDYYFYNHMDVWGKGTTVTVSS
722 312
QSALTQPASVSGSPGQSITISCTGTSSDVVTYNLVSWYQQHPGKAPKLIIYEATKRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCCSYAGTSSVVFGGGTKLTVL
723 313
QVQLVESGGGVVQPGRSLRLSCAASGFTFRSYTMHWVRQAPGKGLEWVAVISYDGSYKYYADSVKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARDVI EYSGSSEYYGMDVWGQGTTVTVSS
724 313
QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSKRPSGVPDRFSGSK
SGNTASLTISGLQAEDEADYYCCSYAGSYTFVVFGGGTKLTVL
725 314
QVQLVESGGGVVQPGRSLRLSCAASGFTFRSYTMHWVRQAPGKGLEWVAVISYDGSYKYYADSVKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARDVI EYSGSSEYYGMDVWGQGTTVTVSS
726 314
QSALTQPASVSGSPGQSITISCTGTSSDVGGHNYVSWYQQYPGKAPKLMIYDVSNRPSGVSNRFSASK
SGNTASLTISGLQAEDEGDYYCSSYTSRSTLVFGGGTKLTVL
727 315
QVQLVESGGGVVQPGRSLRLSCAASGFTFRSYTMHWVRQAPGKGLEWVAVISYDGSYKYYADSVKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARDVI EYSGSSEYYGMDVWGQGTTVTVSS
728 315
DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLYPGVPSRFSGSGSG
TDFTLTISSLQPEDVATYYCQTLTFGGGTKVEIK
729 316
EVHLVESGGGLVKPGESLRLSCEASGFTFTNAWMSWVRQAPGKGLEWIGRIKGESEGGTADYAAPVKG
RFSMSRDNSKNIVYLQMNSLKTEDTATYYCVTKLGTALWVIDYFDNWGQGTLVTVSS
730 316
QSALTQPASVSGSPGQSITISCTGTSSDVGGHNYVSWYQQYPGKAPKLMIYDVSNRPSGVSNRFSASK
SGNTASLTISGLQAEDEGDYYCSSYTSRSTLVFGGGTKLTVL
731 317
EVQLVESGGDLVQPGGSLRLSCAASGFSFSSFSMTWVRQAPGKGLEWVAYISGNGYIIYYTDSVKGRF
TISRDNARNSLYLQLNSLRAEDTAVYFCASWVDSRGYYYVDYFDNWGQGTLVTVFL
732 317
QSVLTQPPSLSAAPGQKVTISCSGSSKIDYVSWYQQFPGTAPKLLIYDNSHRPSGIPDRFSGSKSGTS
ATLGITGLQTGDEADYYCGTWDSRLNVYVFGPGTKVTVL
733 318
QVQLQQKGAALLKPSETLSLTCGVSGGTFSDYHWTWVRQPPGKGLEWIGKINHGGSTNYNPTLKSRVS
ISIDTSKSQFSLKMTSLTAADAAVYFCARLREGRALRLTSQPRYSYYHMDVWGKGTTVTVSS
734 318
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCSSYTSSSTLVFGGRTKLTVL
735 319
EVQLLESGGGSVQPGGSLRLSCAASGFSFSSYVMGWVRQAPGKGLEWVSAISGSGGSTYYANSVKGRF
TISRDNSKNTLSLQMNSLRVEDTAVFYCAKEATGDCGGDCVRWFDPWGQGTLVTVSS
736 319
DIQMTQSPSSVSASIGDRVTITCRASQGINRWLAWYQQKPGKAPRLLIYAASSLQSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYSCQQAQTFPLTFGGGTKVEIK
737 320
EVQLVESGGGLVQPGGSLRLSCAASGFI FSDHYMDWVRQAPGKGLEWVGRSWRKTESATPDYAASVRG
RFTISRDDSQNSLYLQMDSLKTEDTAVYYCATSVGDTADFDYWGQGALVTVSS
738 320
QSVLTQPPSLSAAPGQKVTISCSGSSKIDYVSWYQQFPGTAPKLLIYDNSHRPSGIPDRFSGSKSGTS
ATLGITGLQTGDEADYYCGTWDSRLNVYVFGPGTKVTVL
739 321
EVHLVESGGGLVKPGESLRLSCEASGFTFTNAWMSWVRQAPGKGLEWIGRIKGESEGGTADYAAPVKG
RFSMSRDNSKNIVYLQMNSLKTEDTATYYCVTELGTALWVIDYFDNWGQGTLVTVSS
740 321
DIQMTQSPSPLSASVGDRVTIYCRASQSISNFLNWYQQRPGKAPKLLIYATSSLQSGVSSRFSGHGFG
TEFTLTISSLQPEDFATYYCQQSYTTSQLTFGPGTKVEIK
741 322
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYTDSVKGRF
TISRDNSINTLYLQMNSLRAEDSAVYYCAKDRDRSAYNYGPAMAREYFQHWGQGTLVTVSS
742 322
QSALTQPASVSGSPGQSITISCTGTSSDVGGHNYVSWYQQYPGKAPKLMIYDVSNRPSGVSNRFSASK
SGNTASLTISGLQAEDEGDYYCSSYTSRSTLVFGGGTKLTVL
743 323
EVQLVESGGDLVQPGGSLRLSCAASGFSFSSFSMTWVRQAPGKGLEWVAYISGNGYIIYYTDSVKGRF
TISRDNARNSLYLQLNSLRAEDTAVYFCASWVDSRGYYYVDYFDNWGQGTLVTVSS
744 323
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSLYTFGQGTKLEIK
745 324
EVQLVESGGGSVQPGGSLRLSCTTSGFSFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVEGRF
TISRDNAKNSLYLQMNSLRAEDTAVYFCARDQLGGAVVPADYFDYWGQGTLVTVSS
746 324
SYELTQPPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVLVIYQDSKRPSGIPERFSGSNSGN
TATLTISGTQAMDEADYYCQAWDSSTAVFGGGTKLTVL
747 325
QVQLVESGGGVVQPGRSLRLSCAASGFTFRSYTMHWVRQAPGKGLEWVAVISYDGSYKYYADSVKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARDVI EYSGSSEYYGMDVWGQGTTVTVSS
748 325
SYELTQPPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVLVIYQDSKRPSGIPERFSGSNSGN
TATLTISGTQAMDEADYYCQAWDSSTAVFGGGTKLTVL
749 326
QVQLVESGGGVVQPGRSLRLSCAASGFTLRNYAMHWVRQAPGKGLEWVAVLSYDGNNKKYADSVKGRF
TISRDISNNTLYLHMDSLRAEDRAVYYCARDRTPYSSGWYVGYWGQGTLVTVSS
750 326
DIQMTQSPSSLSAYVGDRVTITCRTSQSISSYLNWYKQKPGEAPKLLMYAASTLQSGVPSRFSGRGSG
TDFTLTISNLQADDSATYYCQQSYSTPPTFGQGTKVEIK
751 327
QVQLVESGGGVVQPGRSLRLSCAASGFTLRNYAMHWVRQAPGKGLEWVAVLSYDGNNKKYADSVKGRF
TISRDISNNTLYLHMDSLRAEDRAVYYCARDRTPYSSGWYVGYWGQGTLVTVSS
752 327
QSALTQPASVSGSPGQSITISCTGTSSDVGGHNYVSWYQQYPGKAPKLMIYDVSNRPSGVSNRFSASK
SGNTASLTISGLQAEDEGDYYCSSYTSRSTLVFGGGTKLTVL
753 328
QVQLVQSGAEVMQVGASVKVSCKASGYTFTLYAMHWVRQAPGQRLEWLGWINAGNGDTKYSQKFQGRV
TITRDTPASTAYMELSSLRSEDTAIYYCARDKEGWNDPNYFDFWGQGTLVTVSS
754 328
QSVLTQPPSVSAAPGQNVTISCSGSSSNIGNYLVSWYQHLPGTAPKLLIYDNNKRPSGIPDRFSGSKS
GTSATLGITGLQTGDEGDYFCGTWDNSLSGGVFGGGTKLTVL
755 329
EVQLVESGGGSVQPGGSLRLSCTTSGFSFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVEGRF
TISRDNAKNSLYLQMNSLRAEDTAVYFCARDQLGGAVVPADYFDYWGQGTLVTVSS
756 329
EIVLTQSPATLSLSPGERATLSCRASVNIAMSLAWFQQKPGQVPRLLIYDASHRATGIPARFSGSGSV
TDFTLTISSLEAEDFAVYYCQQRASWPKVTFGGGTKVEIT
757 330
QVQLQQKGAALLKPSETLSLTCGVSGGTFSDYHWTWVRQPPGKGLEWIGKINHGGSTNYNPTLKSRVS
ISIDTSKSQFSLKMTSLTAADAAVYFCARLREGRALRLTSQPRYSYYHMDVWGKGTTVTVSS
758 330
EIVLTQSPATLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGTPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPYTFGQGTKLEIK
759 331
QVQLVESGGGVVQPGRSLRLSCAASGFTLRNYAMHWVRQAPGKGLEWVAVLSYDGNNKKYADSVKGRF
TISRDISNNTLYLHMDSLRAEDRAVYYCARYRTPYSSGWYVGYWGQGTLVTVSS
760 331
EIVLTQSPATLSLSPGERATLSCRASVNIAMSLAWFQQKPGQVPRLLIYDASHRATGIPARFSGSGSV
TDFTLTISSLEAEDFAVYYCQQRASWPKVTFGGGTKVEIT
761 332
AVQLLESGGGLIQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSAISHSSDSTYYADSVKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCAKPSGSSWSLLYFDYWGQGTLVTVSS
762 332
QSVVTQPPSASGTPGQSVTISCSGSTSNIASSDVYWYQHLPGAAPNLLIYKNNQRPSGVPDRFSGSKS
GTSASLAISGLRAEDEANYYCATWDDSLRGPI FGGGTKLSVI
763 333
EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMHWVRPAPGKGLVVVARISGDGSDADYADSVRGRF
TISRDNAKNTLFLQMNSLRVEDTAVYYCVRDRDVRDCNNGVCHTAYFNYWGQGTLVTVSS
764 333
DIQMTQSPSTLSASVGDRVTITCRASQSISRWLAWHQQKPGKAPNLLIYEASSLESGVPSRFSGSGSG
TEFTFTISSLQPDDFATYYCQHYKSYPLTFGGGTKVEIK
765 334
QLQLVESGGGVVQTGRSLRLSCLASGFTLSGFAMHWVRQTPHKGLEWVAVISSDGGDIYYADSVKGRF
TISRDNFKNTI FLQMNNLRGDDTAVYFCVRPQSQLDRSGSSYFVAFDIWGQGTMVTVSS
766 334
EIVLTQSPGTLSLSPGERATLSCRASQNVIRDYLAWYQQKPGQAPRLLI FGTSNRATGIPDRFSGSGS
GTDFTLTINRLAPDDFAVYYCQHYGSSLFTFGPGTKLDIK
767 335
QVHLVESGGGVVQPGRSLRLSCAASGFSFSSYGLHWVRQAPGKGLEWVAFISHVGSNKYYADSVKGRF
TISRDNSKNTLYLQMNSLRTEDTAVYYCAREHTVGGI FGFWGQGTLVTVSS
768 335
QSVLTQPPSASGTPGQRVTISCSGSSSNIGSYTVNWYQQLPGTAPKLLIYNNNQRPSGVPDRFSGSKS
GTSASLAISGLQSEDEADYYCAAWDDSLNGHVVFGGGTKLTVL
769 336
QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYHDYALSVK
SRITINPDTSKNQFSLQLNSVTPEDTAVYYCARAAWEGGGYQLVLYYSYYYGMDVWGQGTTVTVSS
770 336
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSK
SGTSASLAITGLQAEDEDDYYCQSYDSRLSGWVFGGGTKLTVL
771 337
QVHLVESGGGVVQPGRSLRLSCAASGFSFSSYGLHWVRQAPGKGLEWVAFISYVGSNKYYADSVKGRF
TISRDNSKNTLYLQMNSLRTEDTAVYYCAREYTVGGI FGFWGQGTLVTVSS
772 337
QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSKRPSGVPDRFSGSK
SGNTASLTISGLQAEDEADYYCCSYAGSYTHVVFGGGTKLTVL
773 338
QVQLVQSGAEVMQVGASVKVSCKTSGYTFTSYYLHWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRV
TMTRDTSTSTVYMELSSLRSEDTAVYYCARGALTMVRAVEYFQHWGQGTLVTVSS
774 338
DIQMTQSPSTLSASVGDRVTITCRASQSISRWLAWHQQKPGKAPNLLIYEASSLESGVPSRFSGSGSG
TEFTFTISSLQPDDFATYYCQHYKSYPLTFGGGTKVEIK
775 339
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDHYMDWVRQAPGKGLEWVGRTRNRAKSYTTEYAASVKG
RFTISRDDSKNSLYLQMNSLKTEDTAVYYCARARPLGGSGTNYSMDVWDQGTTVTVSS
776 339
DIQMTQSPSTLSASVGDRVSITCRASQSISTWLAWYQQKPGKAPKLLIYKASSLQSGVPSRFSGSGSG
TVFTLTISSLQPDDFATYYCQQYNSYSRTFGQGTKVEIK
777 340
EVQLLESGGGLVQPGGSLRLSCAASGFTFNIYAINWVRQAPGKGLEWVSSISGSGDSAYYADSVKGRF
TISRDNSKNTVFLQMNSLTAEDTAVYYCAKQYCTNGVCYTDYYFYNHMDVWGKGTTVTVSS
778 340
QSVLTQPPSASGTPGQRVTISCSGSSSNIGSYTVNWYQQLPGTAPKLLIYNNNQRPSGVPDRFSGSKS
GTSASLAISGLQSEDEADYYCAAWDDSLNGHVVFGGGTKLTVL
779 341
QVQLVQSGAEVMQVGASVKVSCKTSGYTFTSYYLHWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRV
TMTRDTSTSTVYMELSSLRSEDTAVYYCARGALTMVRAVEYFQHWGQGTLVTVSS
780 341
QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSKRPSGVPDRFSGSK
SGNTASLTISGLQAEDEADYYCCSYAGSYTHVVFGGGTKLTVL
781 342
QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVT
ISVDTSKNQFSLKLSSVTAADTAVYYCARAPRTTVTTGRWFDPWGQGTLVTVSS
782 342
EVVLTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGFPARFSGSGSG
TEFTLTISSLQSEDFAIYHCQQYNNWPLTFGGGTKVEIK
783 343 QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYHDYALSVK
SRITINPDTSKNQFSLQLNSVTPEDTAVYYCARAAWEGGGYQLVLYYSYYYGMDVWGQGTTVTVSS
784 343
QSVVTQPPSASGTPGQSVTISCSGSTSNIASSDVYWYQHLPGAAPNLLIYKNNQRPSGVPDRFSGSKS
GTSASLAISGLRAEDEANYYCATWDDSLRGPI FGGGTKLSVI
785 344
QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVT
ISVDTSKNQFSLKLSSVTAADTAVYYCARLRRDIVVVPAANRGGGSSWQNYYYYYMDVWGKGTTVTVS S
786 344
AIRMTQSPSSFSASTGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSG
TDFTLTISCLQSEDFATYYCQQYYSYPRTFGQGTKVEIK
787 345
QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSESVAWNWIRQSPSRGLEWLGRTYYRSRWYSDYAVSVK
SRITINPDTSKNQFSLQVSSMTPEDTAVYYCARMFSSSGHFDYWGQGTLVTVSS
788 345
QSVLTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCSSYTSSSTPVFGGGTKLTVL
789 346
QLQLVESGGGVVQTGRSLRLSCLASGFTLSGFAMHWVRQTPHKGLEWVAVISSDGGDIYYADSVKGRF
TISRDNFKNTI FLQMNNLRGDDTAVYFCVRPQSQLDRSGSSYFVTFDIWGQGTMVTVSS
790 346 EIVMTQSPATLSVSPGERATLSCRASQSISTNLAWYQQKPGQAPRVLIYGASTRATDVPDRFSGTGSG
TDFTLTISSLQSEDFAIYYCQQYHNWPPETFGQGTKVEIK
791 347
QVQLQESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEIYHSGSTNYNPSLKSRV
TISVDKSKNQFSLKLSSVTAADTAVYYCARDEGGVGGWFDPWGQGTLVTVSS
792 347
EIVLTQSPGTLSLSPGERATLSCRASQNVIRDYLAWYQQKPGQAPRLLI FGTSNRATGIPDRFSGSGS
GTDFTLTINRLAPDDFAVYYCQHYGSSLFTFGPGTKLDIK
793 348
KIQLQESGPGLVKPSQTLSPTCTVSGGSLSSGDYYWSWIRQPPGKGLEWIGYIYYSGSTSHNPSLKSR
VSISVDTSKNQFSLKLSSVSAADTAVYYCARYYYATSGFYERPPGPRFNWFDPWGQGTLVTVSS
794 348 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYGASNRATGIPARFSGSGSG
TDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK
795 349
EVHLVESGGGLVKPGESLRLSCEASGFTFTNAWMSWVRQAPGKGLEWIGRIKGESEGGTADYAAPVKG
RFSMSRDNSKNIVYLQMNSLKTEDTATYYCVTELGTALWVIDYFDNWGQGTLVTVSS
796 349
DIQMTQSPSSLSASVGDRVTITCRASQSISNYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSG
TDFTLTISSLQPENFATYYCQQSYSAPHTFGPGTKVDIK
797 350
QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSESVAWNWIRQSPSRGLEWLGRTYYRSRWYSDYAVSVK
SRITINPDTSKNQFSLQVSSMTPEDTAVYYCARVFSSSGHFDYWGQGTLVTVSS
798 350
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSK
SGTSASLAITGLQAEDEDDYYCQSYDSRLSGWVFGGGTKLTVL
799 351
QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSESVAWNWIRQSPSRGLEWLGRTYYRSRWYSDYAVSVK
SRITINPDTSKNQFSLQVSSMTPEDTAVYYCARVFSSSGHFDYWGQGTLVTVSS
800 351
EVVLTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGFPARFSGSGSG
TEFTLTISSLQSEDFAIYHCQQYNNWPLTFGGGTKVEIK
801 352
QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVT
ISVDTSKNQFSLKLSSVTAADTAVYYCARAPRTTVTTGRWFDPWGQGTLVTVSS
802 352
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSK
SGTSASLAITGLQAEDEDDYYCQSYDSRLSGWVFGGGTKLTVL
803 353
EVQLVESGGDLVQPGGSLRLSCAASGFTFSNYWMHWVRPAPGKGLVVVARISGDGSDADYADSVRGRF
TISRDNAKNTLFLQMNSLRVEDTAVYYCVRDRDVRDCNNGVCHTAYFNYWGQGTLVTVSS
804 353
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSK
SGTSASLAITGLQAEDEDDYYCQSYDSRLSGWVFGGGTKLTVL
805 354
QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSESVAWNWIRQSPSRGLEWLGRTYYRSRWYSDYAVSVK
SRITINPDTSKNQFSLQVSSMTPEDTAVYYCARVFSSSGHFDYWGQGTLVTVSS
806 354
DIQMTQSPSSVSASIGDRVTITCRASQGINRWLAWYQQKPGKAPRLLIYAASSLQSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYSCQQAQTFPLTFGGGTKVEIK
807 355
QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVT
ISVDTSKNQFSLKLSSVTAADTAVYYCARLRRDIVVVPAANRGGGSRWQNYYYYYMDVWGKGPIGL
808 355
SYELTQPPSVSVAPGKTARITCGGDNIGSKSVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGN
TATLTISRVEAGDEADFYCQVWDGSSDHVVFGGGTKLTVL
809 356
QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVT
ISVDTSKNQFSLKLSSVTAADTAVYYCARLRRDIVVVPAANRGGGSSWQNYYYYMDVWGKGTTVTVSS
810 356
SFMLTQPHSVSESPGKTVTISCTRSSGSIASNYVQWYQQRPGSSPTTVIYENNQRPSGVPDRFSGSID
SSSNSASLTISGLKTEDEADYYCHSYDANKRGVFGGGTKLTVL
811 357
QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYAMHWVRQAPGKGLEWVAVI LDDGSNKYYADSVKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCARASEMATI EDAFDIWGQGTMVTVSL
812 357
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK
813 358
QLQLQESGPGLVNPWETLTLTCSVSGASISSISYNWGWVRQPPGKGLEWIGNIYFTGTTHYNPSLNSR
VTISVDTSRNQFSLTLSSVTAADTAMYYCVREGQTVTTWFDPWGQGTLVTVSS
814 358
EIVLTQSPGTLSLSPGERATLSCRASQNVIRDYLAWYQQKPGQAPRLLI FGTSNRATGIPDRFSGSGS
GTDFTLTINRLAPDDFAVYYCQHYGSSLFTFGPGTKLDIK
815 359
EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYATTWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCATVKQWLALDYWGQGTLVTVSS
816 359
SYELTQPPSVSVAPGKTARITCGGDNIGSKSVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGN
TATLTISRVEAGDEADFYCQVWDGSSDHVVFGGGTKLTVL
817 360
QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVT
ISVDTSKNQFSLKLSSVTAADTAVYYCARARPLGGSGTNYGMDVWGQGTTVTVSS
818 360
SYELTQPPSVSVAPGKTARITCGGDNIGSKSVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGN
TATLTISRVEAGDEADFYCQVWDGSSDHVVFGGGTKLTVL
819 361
QVQLVQSGAEVMQVGASVKVSCKTSGYTFTSYYLHWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRV
TMTRDTSTSTVYMELSSLRSEDTAVYYCARGALTMVRAVEYFQHWGQGTLVTVSS
820 361
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYGASNRATGIPARFSGSGSG
TDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK
821 362
EVQLVESGGGLVQPGGSLRLSCAASGFI FSDHYMDWVRQAPGKGLEWVGRSWRKTESATPDYAASVRG
RFTISRDDSQNSLYLQMDSLKTEDTAVYYCATSVGDTADFDYWGQGALVTVSS
822 362
DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRFSGSGSG
TDFTLTISSLQPEDVATYYCQKYNSAPPWTFGQGTKVEIK
823 363
QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSESVAWNWIRQSPSRGLEWLGRTYYRSRWYSDYAVSVK
SRITINPDTSKNQFSLQVSSMTPEDTAVYYCARVFSSSGHFDYWGQGTLVTVSS
824 363
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPPYTFGQGTKLEIK
825 364
QIQLQESGPGLVKPSQTLSLTCTVSGGSLSSGDYYWSWIRQPPGKGLEWIGYIYYSGSTSHNPSLKSR
VSISVDTSKNQFSLKLSSVSAADTAVYYCARYYYATSGFYERPPGPRFNWFDPWGQGTLVTVSS
826 364
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSK
SGTSASLAITGLQAEDEDDYYCQSYDSRLSGWVFGGGTKLTVL
827 365
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDHYMDWVRQAPGKGLEWVGRTRNRAKSYTTEYAASVKG
RFTISRDDSKNSLYLQMNSLKTEDTAVYYCARARPLGGSGTNYGMDVWGQGTTVTVSS
828 365 EVVLTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGFPARFSGSGSG
TEFTLTISSLQSEDFAIYHCQQYNNWPLTFGGGTKVEIK
829 366
QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYHDYALSVK
SRITINPDTSKNQFSLQLNSVTPEDTAVYYCARAAWEGGGYQLVLYYSYYYGMDVWGQGTTVTVSS
830 366
AIRMTQSPSSFSASTGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSG
TDFTLTISCLQSEDFATYYCQQYYSYPRTFGQGTKVEIK
831 367
QVQLVQSGAEVMQVGASVKVSCKTSGYTFTSYYLHWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRV
TMTRDTSTSTVYMELSSLRSEDTAVYYCARGALTMVRAVEYFQHWGQGTLVTVSS
832 367
SFMLTQPHSVSESPGKTVTISCTRSSGSIASNYVQWYQQRPGSSPTTVIYENNQRPSGVPDRFSGSID
SSSNSASLTISGLKTEDEADYYCHSYDANKRGVFGGGTKLTVL
833 368
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDHYMDWVRQAPGKGLEWVGRTRNRAKSYTTEYAASVKG
RFTISRDDSKNSLYLQMNSLKTEDTAVYYCARARPLGGSGTNYGMDVWGQGTTVTVSS
834 368
DIQMTQSPSTLSASVGDRVSITCRASQSISTWLAWYQQKPGKAPKLLIYKASSLQSGVPSRFSGSGSG
TVFTLTISSLQPDDFATYYCQQYNSYSRTFGQGTKVEIK
835 369
QVQLQESGPGLVKPSETLSLTCTVSTGTVRDNMFYWGWIRQSPGKGLEWIGSVFFLGTTYYNPSFKSR
ATI FVNLSKNQFSLELTSVTAADTAVYYCARENYGDSQRDYHYGMDVWGPGLRVTVSS
836 369
EIVMTQSPATLSVSPGEGVTLSCRASRTISNNVAWFQVKPGQGPRLLIYGASNRAAGIPLRFSGSGSG
TEFTLTISSVQSEDFAVYYCQHYNNWPGYTFGQGTKLDIK
837 370
QVHLVESGGGVVQPGRSLRLSCAASGFSFSSYGLHWVRQAPGKGLEWVAFISYVGSNKYYADSVKGRF
TISRDNSKNTLYLQMNSLRTEDTAVYYCAREYTVGGI FGFWGQGTLVTVSS
838 370
SFMLTQPHSVSESPGKTVTISCTRSSGSIASNYVQWYQQRPGSSPTTVIYENNQRPSGVPDRFSGSID
SSSNSASLTISGWKTEDEADYYCHSYDANKRGVFGGGTKLTVL
839 371
EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYATTWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRF
TISRDNSKNTLYLQMNSLRAGTRPYITVQPSSSGWHLTIGAREPWSPSP
840 371
SYELTQPPSMSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVLVIYQDNKRPSGIPERFSGSNSGN
TATLTISGTQAMDEADYYCQAWDSGTVLFGGGTKLTVL
841 372
EVQLLESGGGLVQPGGSLRLSCAASGFTFNIYAINWVRQAPGKGLEWVSSISGSGDSAYYADSVKGRF
TISRDNSKNTVFLQMNSLTAEDTAVYYCAKQYCTNGVCYTDYYFYNHMDVWGKGTTVTVSS
842 372
EIVLTQSPATLSLSPGERTTLSCRASQSVSSYLAWYQQKPGQAPRLLIYGASNRATGIPARFSGSGSG
TDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK
843 373
QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYHDYALSVK
SRITINPDTSKNQFSLQLNSVTPEDTAVYYCARAAWEGGGYQLVLYYSYYYGMDVWGQGTTVTVSS
844 373
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLGWYQHKPGQAPRLLIYDTSNRATGIPARFSGSGSG
TDFI LTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK
845 374
EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYATTWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCATVKQWLALDYWGQGTLVTVSS
846 374
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSK
SGTSASLAITGLQAEDEDDYYCQSYDSRLSGWVFGGGTKLTVL
847 375
QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSESVAWNWIRQSPSRGLEWLGRTYYRSRWYSDYAVSVK
SRITINPDTSKNQFSLQVSSMTPEDTAVYYCARVFSSSGHFDYWGQGTLVTVSS
848 375
DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSNGYNSLDWYLQKPGQSPQLLIYLGSNRASGVPDRFS
GSGSGTDFTLKISRVEAEDVGVYYCMEALQTPYTFGQGTKLEIK
849 376
QVQLVESGGGVVQPGMSLRLSCAASGFTFNSYAIHWVRQAPGKGLEWVAVISYDETSNFYTDSVKGRF
TISRDNSKNTVYLQMNSLGVDDTAVYYCARDFYPGSGTNWATNRFDPWGQGTLVTVSS
850 376
DIQMTQSPSSLSASVGDRVTITCRASQSVSTYFNWYQHKPGKAPKLLIYAASSLQSGVPSRFTGSGSG
TDFTLTISSLQPEDFATYYCQQSYSTPYTFGQGTKLEIK
851 377
QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVT
ISVDTSKNQFSLKLSSVTAADTAVYYCARAPRTTVTTGRWFDPWGQGTLVTVSS
852 377
DIQMTQSPSSLSASVGDRVTITCRASQSVSTYFNWYQHKPGKAPKLLIYAASSLQSGVPSRFTGSGSG
TDFTLTISSLQPEDFATYYCQQSYSTPYTFGQGTKLEIK
853 378
EVQLVESGGGLVQPGGSLRLPCAASGFTFRTYGMNWVRQAPGKGLEWISYISSSGSTIYYADSVKGRF
TISRDNAKNSLFLQMNSLRAEDTAVYYCARGFRRITIRPGNYYYYMDVWGKGTTVTVSS
854 378
SYELTQPPSVSVAPGKTARITCGGDNIGSKSVHWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSNSGN
TATLTISRVEAGDEADFYCQVWDGSSDHVVFGGGTKLTVL
855 379
EVQLVESGGGLVQPGGSLRLPCAASGFTFRTYGMNWVRQAPGKGLEWISYISSSGSTIYYADSVKGRF
TISRDNAKNSLFLQMNSLRAEDTAVYYCARGFRRITIRPGNYYYYMDVWGKGTTVTVSS
856 379
SFMLTQPHSVSESPGKTVTISCTRSSGSIASNYVQWYQQRPGSSPTTVIYENNQRPSGVPDRFSGSID
SSSNSASLTISGLKTEDEADYYCHSYDANKRGVFGGGTKLTVL
857 380
QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVT
ISVDTSKNQFSLKLSSVTAADTAVYYCARVLRLGELSFRNWGQGTLVTVSS
858 380
AIRMTQSPSSFSASTGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSG
TDFTLTISCLQSEDFATYYCQQYYSYPRTFGQGTKVEIK
859 381
QLQLVESGGGVVQTGRSLRLSCLASGFTLSGFAMHWVRQTPHKGLEWVAFISSDGGDIYYADSVKGRF
TISRDNFKNTI FLQMNNLRGDDTAVYFCVRPQSQLDRSGSSYFVAFDIWGQGTMVTVSS
860 381
SYELTQPPSVSVSPGQTASITCSGDKLGDKYTSWYHQKPGQSPVLVIYQNTKRPSGIPERFSGSNSGN
TATLTISGTQAMDEADYYCQAWDSSTAVFGGGTKLTVL
861 382
QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYLSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRIT
ISVATSKNQFSLKLSSVTAADTAVYYCTRARPLGGSGTNYGMDVWGQGSTVTVSS
862 382
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCSSYTSSSTLVFGGGTKLTVL
863 383
QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVT
ISVDTSKNQFSLKLSSVTAADTAVYYCAKADGTSTVTTFSDYWGQGTLVIVSS
864 383
SFMLTQPHSVSESPGKTVTISCTRSSGSIASNYVQWYQQRPGSSPTTVIYENNQRPSGVPDRFSGSID
SSSNSASLTISGLKTEDEADYYCHSYDANKRGVFGGGTKLTVL
865 384
EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYATTWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRF
TISRDNSKNTLYLQMNSLRAEDTAVYYCATVKQWLALDYWGQGTLVTVSS
866 384
EIVMTQSPATLSVSPGEGVTLSCRASRTISNNVAWFQVKPGQGPRLLIYGASNRAAGIPLRFSGSGSG
TEFTLTISSVQSEDFAVYYCQHYNNWPGYTFGQGTKLDIK
867 385
QLQLQESDSGLVKPSQTLSLTCAVSGGSISSGGYSWSWIRQPPGKGLEWIGFIYQSGTTSYNPSLKSR
VTISVDRSKNQFSLKLSSVTAADTAVYYCARELGRGTAFEIWGQGTMVTVSS
868 385
QSALTQPASVSGSPGQSITISCTGTSSDIGAYNYVSWFQQHPGKAPKLMIYDVNYRPSGVPNRFSGSK
SGNTASLTISGLQAEDEADYYCTSYTSSSTLVVFGGGTRLTVL
869 386
EVQLVESGGGLVQTGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVASVKGRF
TISRDNAKKSLYLQMNSLRAEDTAVYYCARDWEGDGSFWSGFFPTPAQKYGMDVWGQGTTVTVSS
870 386
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYGASNRATGIPARFSGSGSG
TDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK
871 387
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDHYMDWVRQAPGKGLEWVGRTRNRAKSYTTEYAASVKG
RFTISRDDSKNSLYLQMNSLKTEDTAVYYCARARPLGGSGTNYGMDVWGQGTTVTVSS
872 387
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPPYTFGQGTKLEIK
873 388
QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRFT
ISVATPKNHFSLKLSSVTAADTAVYYCARHFAARPGYFDYWGQGTLVTVSS
874 388
SYELTQPPSVSVSLGQMARITCSGEALPKKYAYWYQQKPGQFPVLVIYKDSERPSGIPERFSGSSSGT
IVTLTISGVQAEDEADYYCLSADSSGTYWVFGGGTKLTVL
875 389
QLQLQESGPGLVKPSETLSLPCTVFGVSISSNSYYWGWIRQPPGKGLEWIGSINYSGNTYYNPSLKSR
VTISVDTFKNQFSLKLSPVTAADTGMFYCARLPPPRGSAAGRYYFDSWGLGTLVTVSS
876 389
SFMLTQPHSVSESPGKTVTISCTRSSGSIASNYVQWYQQRPGSSPTTVIYENNQRPSGVPDRFSGSID
SSSNSASLTISGLKTEDEADYYCHSYDANKRGVFGGGTKLTVL
877 390
QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYHDYALSVK
SRITINPDTSKNQFSLQLNSVTPEDTAVYYCARAAWEGGGYQLVLYYSYYYGMDVWGQGTTVTVSS
878 390
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYGASNRATGIPARFSGSGSG
TDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK
879 391
QLQLVESGGGVVQTGRSLRLSCLASGFTLSGFAMHWVRQTPHKGLEWVAVISSDGGDIYYADSVKGRF
TISRDNFKNTI FLQMNNLRGDDTAVYFCVRPQSQLDRSGSSYFVAFDIWGQGTMVTVSS
880 391
EIVMTQSPATLSVSPGEGVTLSCRASRTISNNVAWFQVKPGQGPRLLIYGASNRAAGIPLRFSGSGSG
TEFTLTISSVQSEDFAVYYCQHYNNWPGYTFGQGTKLDIK
881 392
QLQLVESGGGVVQTGRSLRLSCLASGFTLSGFAMHWVRQTPHKGLEWVAVISSDGGDIYYADSVKGRF
TISRDNFKNTI FLQMNNLRGDDTAVYFCVRPQSQLDRSGSSYFVAFDIWGQGTMVTVSS
882 392
QLVLTQPPSASGSPGQRVTLSCSGGSSNIGKNYVYWYQHVPGTAPRLLIYRDHQRPSGVPDRFSGSKS
GTSASLAISGLRSEDEADYYCAAWDGSLSGPYVFGTGTKVTVL
883 393
QVQLVQSGAEVMQVGASVKVSCKTSGYTFTSYYLHWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRV
TMTRDTSTSTVYMELSSLRSEDTAVYYCAREALTMVRAVEYFQHWGQGTLVTVSS
884 393
DIQMTQSPSSLSASVGDRVTITCRASQSISNYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSG
TDFTLTISSLQPENFATYYCQQSYSAPHTFGPGTKVDIK
885 394
EEQLVESGGGLVQPGGSLRLSCAASGFNFSSFWMHWVRQAPGKGLVWVSRIDSAGATTTYADSVKGRF
TISRDNANNTLYLQMSSLRAEDTAVYYCARLSSAPWSGFYVWHANWFDPWGQGTLVTVSS
886 394 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYGASNRATGIPARFSGSGSG
TDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK
887 395
QVQLEESGAGLVQPGGSRCLSCAASGCTFSSYWMSWVRQAPGKGLEWVGNIKQGGSANYYVASVKGGF
TITRDNAKKSLYLQMNSLGAEDTAVYYCARDWEGDGSFWSGFFPTTAQKYDMDVWGKGTTVTVSS
888 395
SFMLTQPHSVSESPGKTVTISCTRSSGSIASNYVQWYQQRPGSSPTTVIYENNQRPSGVPDRFSGSID
SSSNSASLTISGLKTEDEADYYCHSYDANKRGVFGGGTKLTVL
889 396
QVQLQESGPGLVKPSETLSLTCTVYGGSISSFYWSWIRQPPGKGLEWIGYIYYSGNTNYNPSLKSRVT
ISIDTSKNQFSLKLSSVTAADTAVYYCANSYGTGSYYHWGQGTLVTVSS
890 396
SYELTQPPSVSVSPGQTARITCSGDALPKKYAYWYQQKSGQAPVLVIYEDSKRPSGIPERFSGSSSGT
MATLTISGAQVEDEADYYCYSTDSSGNHWVFGGGTKLTVL
891 397
QLQLQESGPGLVKPSETLSLPCTVFGVSISSNSYYWGWIRQPPGKGLEWIGSINYSGNTYYNPSLKSR
VTISVDTFKTHFSLKLSPVTAADTGMFYCARLPPPRGSAAGRYYFDSWGLGTLVTVSS
892 397
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS
GTDFTLTISRLEPEDFAVYYCQQYGSSPPYTFGQGTKLEIK
893 398
QVHLVESGGGVVQPGRSLRLSCAASGFSFSSYGLHWVRQAPGKGLEWVAFISYVGSNKYYADSVKGRF
TISRDNSKNTLYLQMNSLRTEDTAVYYCAREYTVGGI FGFWGQGTLVTVSS
894 398
DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSNGYNSLDWYLQKPGQSPQLLIYLGSNRASGVPDRFS
GSGSGTDFTLKISRVEAEDVGVYYCMEALQTPYTFGQGTKLEIK
895 399
QLQLQESDSGLVKPSQTLSLTCAVSGGSISSGGYSWSWIRQPPGKGLEWIGFIYQSGTTSYNPSLKSR
VTISVDRSKNQFSLKLSSVTAADTAVYYCARELGRGTAFEIWGQGTMVTVSS
896 399
EIVLTQSPGTLSLSPGERATLSCRASQNVIRDYLAWYQQKPGQAPRLLI FGTSNRATGIPDRFSGSGS
GTDFTLTINRLAPDDFAVYYCQHYGSSLFTFGPGTKLDIK
897 400
QVQLLESGGGLVQPGGSLSLSCAASGFTFSTYSTTWVRQAPGKGLEWFSAISGSGGSTYYADSVKGRF
TISRDNSKNTVYLRVSSLRAEDTAVYYCAGARPLGGSGTNYGMDVWGQGTTVTVSS
898 400
SFMLTQPHSVSESPGKTVTISCTRSSGSIASNYVQWYQQRPGSSPTTVIYENNQRPSGVPDRFSGSID
SSSNSASLTISGLKTEDEADYYCHSYDANKRGVFGGGTKLTVL
899 401
EVQLVESGGGLVQPGGSLRLSCAASGFI FSDHYMDWVRQAPGKGLEWVGRSWRKTESATPDYAASVRG
RFTISRDDSQNSLYLQMDSLKTEDTAVYYCATSVGDTADFDYWGQGALVTVSS
900 401
DIQMTQSPSTLSASVGDRVSITCRASQSISTWLAWYQQKPGKAPKLLIYKASSLQSGVPSRFSGSGSG
TVFTLTISSLQPDDFATYYCQQYNSYSRTFGQGTKVEIK
901 402
QLHLQESGPGLVKPAETLSLTCTVSGASIRSSDYYWVWIRQPPGKGLEWIGSIYHGGSTYYNSSLKSR
VTVSADASTNQFSLRLNSVNAADTAVYYCSSRGLRVPAIWGQGTLVTVPS
902 402
AIRMTQSPSSFSASTGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSG
TDFTLTISCLQSEDFATYYCQQYYSYPRTFGQGTKVEIK
Ab Ab Antigen Specificity
Index Var 1 1 SARS-CoV-1 RBD, SARS-CoV-1 Spike T rimer, SARS-CoV-2
Spike Trimer,
2 1 SARS-CoV-1 RBD, SARS-CoV-1 Spike T rimer, SARS-CoV-2 Spike Trimer,
3 2 SARS-CoV-1 RBD, SARS-CoV-1 Spike T rimer, SARS-CoV-2 RBD, SARS-CoV-2 Spike Trimer,
4 2 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 RBD, SARS-CoV-2 Spike Trimer,
5 3 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 RBD, SARS-CoV-2 Spike Trimer,
6 3 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 RBD, SARS-CoV-2 Spike Trimer,
7 4 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 RBD, SARS-CoV-2 Spike Trimer,
8 4 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 RBD, SARS-CoV-2 Spike Trimer,
9 5 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 RBD,
10 5 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 RBD,
11 6 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 RBD,
12 6 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 RBD,
13 7 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 Spike Trimer,
14 7 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 Spike Trimer,
15 8 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
16 8 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
17 9 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 RBD,
18 9 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 RBD,
19 10 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
20 10 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
21 11 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
22 11 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
23 12 SARS-CoV-2 RBD,
24 12 SARS-CoV-2 RBD,
25 13 SARS-CoV-2 RBD,
26 13 SARS-CoV-2 RBD,
27 14 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 RBD, SARS-CoV-2 Spike Trimer,
28 14 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 RBD, SARS-CoV-2 Spike Trimer,
29 15 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 RBD, SARS-CoV-2 Spike Trimer,
30 15 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 RBD, SARS-CoV-2 Spike Trimer,
31 16 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2 RBD, SARS-CoV-2 Spike Trimer,
32 16 SARS-CoV-1 RBD, SARS-CoV-1 Spike T rimer, SARS-CoV-2
RBD, SARS-CoV-2 Spike Trimer,
33 17 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
34 17 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
35 18 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
36 18 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
37 19 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD, SARS-CoV-2 Spike Trimer,
38 19 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD, SARS-CoV-2 Spike Trimer,
39 20 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD, SARS-CoV-2 Spike Trimer,
40 20 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD, SARS-CoV-2 Spike Trimer,
41 21 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
42 21 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
43 22 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
44 22 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
45 23 link CoV,
46 23 link CoV,
47 24 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
48 24 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
49 25 SARS-CoV-1 RBD,
50 25 SARS-CoV-1 RBD,
51 26 link CoV,
52 26 link CoV,
53 27 link CoV,
54 27 link CoV,
55 28 link CoV,
56 28 link CoV,
57 29 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
58 29 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
59 30 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
60 30 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
61 31 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD, SARS-CoV-2 Spike Trimer,
62 31 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD, SARS-CoV-2 Spike Trimer,
63 32 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
64 32 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
65 33 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
66 33 SARS-CoV-1 RBD, SARS-CoV-1 Spike T rimer, SARS-CoV-2
RBD,
67 34 SARS-CoV-1 RBD, SARS-CoV-1 Spike T rimer, SARS-CoV-2
RBD,
68 34 SARS-CoV-1 RBD, SARS-CoV-1 Spike T rimer, SARS-CoV-2
RBD,
69 35 link CoV,
70 35 link CoV,
71 36 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
72 36 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
73 37 SARS-CoV-1 RBD, SARS-CoV-1 Spike T rimer, SARS-CoV-2
RBD, SARS-CoV- Spike Trimer,
74 37 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD, SARS-CoV- Spike Trimer,
75 38 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
76 38 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
77 39 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
78 39 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
79 40 link CoV,
80 40 link CoV,
81 41 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
82 41 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
83 42 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
84 42 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
85 43 SARS-CoV-1 RBD,
86 43 SARS-CoV-1 RBD,
87 44 link CoV,
88 44 link CoV,
89 45 link CoV,
90 45 link CoV,
91 46 link CoV,
92 46 link CoV,
93 47 link CoV,
94 47 link CoV,
95 48 link CoV,
96 48 link CoV,
97 49 link CoV,
98 49 link CoV,
99 50 link CoV,
100 50 link CoV,
101 51 link CoV,
102 51 link CoV,
103 52 link CoV,
104 52 link CoV,
105 53 link CoV,
106 53 link CoV,
54 link CoV,
54 link CoV,
55 link CoV,
55 link CoV,
56 link CoV,
56 link CoV,
57 link CoV,
57 link CoV,
58 link CoV,
58 link CoV,
59 link CoV,
59 link CoV,
60 link CoV,
60 link CoV,
61 link CoV,
61 link CoV,
62 link CoV,
62 link CoV,
63 link CoV,
63 link CoV,
64 link CoV,
64 link CoV,
65 link CoV,
65 link CoV,
66 link CoV,
66 link CoV,
67 link CoV,
67 link CoV,
68 link CoV,
68 link CoV,
69 link CoV,
69 link CoV,
70 link CoV,
70 link CoV,
71 link CoV,
71 link CoV,
72 link CoV,
72 link CoV,
73 link CoV,
73 link CoV,
74 link CoV,
74 link CoV,
75 link CoV,
75 link CoV,
76 link CoV,
76 link CoV,
77 link CoV,
77 link CoV,
78 link CoV,
78 link CoV,
79 link CoV,
79 link CoV,
80 link CoV,
80 link CoV,
81 link CoV,
81 link CoV,
82 link CoV,
82 link CoV,
83 link CoV,
83 link CoV,
84 link CoV,
84 link CoV,
85 link CoV,
85 link CoV,
86 link CoV,
86 link CoV,
87 link CoV,
87 link CoV,
88 link CoV,
88 link CoV,
89 link CoV,
89 link CoV,
90 link CoV,
90 link CoV,
91 link CoV,
91 link CoV,
92 link CoV,
92 link CoV,
93 link CoV,
93 link CoV,
94 link CoV,
94 link CoV,
95 link CoV,
95 link CoV,
96 link CoV,
96 link CoV,
97 link CoV,
97 link CoV,
98 link CoV,
98 link CoV,
99 link CoV,
99 link CoV,
100 link CoV,
100 link CoV,
101 link CoV,
101 link CoV,
102 link CoV,
102 link CoV,
103 link CoV,
103 link CoV,
104 link CoV,
104 link CoV,
105 link CoV,
105 link CoV,
106 link CoV,
106 link CoV,
107 link CoV,
107 link CoV,
108 Unk CoV,
108 Unk CoV,
109 Unk CoV,
109 Unk CoV,
110 Unk CoV,
110 Unk CoV,
111 Unk CoV,
111 Unk CoV,
112 Unk CoV,
112 Unk CoV,
113 Unk CoV,
113 Unk CoV,
114 Unk CoV,
114 Unk CoV,
115 Unk CoV,
115 Unk CoV,
116 Unk CoV,
116 Unk CoV,
117 Unk CoV,
117 Unk CoV,
118 Unk CoV,
118 Unk CoV,
119 Unk CoV,
119 Unk CoV,
120 Unk CoV,
120 Unk CoV,
121 Unk CoV,
121 Unk CoV,
122 Unk CoV,
122 Unk CoV,
123 Unk CoV,
123 Unk CoV,
124 Unk CoV,
124 Unk CoV,
125 Unk CoV,
125 Unk CoV,
126 Unk CoV,
126 Unk CoV,
127 Unk CoV,
127 Unk CoV,
128 Unk CoV,
128 Unk CoV,
129 Unk CoV,
129 Unk CoV,
130 Unk CoV,
130 Unk CoV,
131 Unk CoV,
131 Unk CoV,
132 Unk CoV,
132 Unk CoV,
133 Unk CoV,
133 Unk CoV,
134 Unk CoV,
134 Unk CoV,
135 link CoV,
135 Unk CoV,
136 Unk CoV,
136 Unk CoV,
137 Unk CoV,
137 Unk CoV,
138 Unk CoV,
138 Unk CoV,
139 Unk CoV,
139 Unk CoV,
140 Unk CoV,
140 Unk CoV,
141 Unk CoV,
141 Unk CoV,
142 Unk CoV,
142 Unk CoV,
143 Unk CoV,
143 Unk CoV,
144 Unk CoV,
144 Unk CoV,
145 Unk CoV,
145 Unk CoV,
146 Unk CoV,
146 Unk CoV,
147 Unk CoV,
147 Unk CoV,
148 Unk CoV,
148 Unk CoV,
149 Unk CoV,
149 Unk CoV,
150 Unk CoV,
150 Unk CoV,
151 Unk CoV,
151 Unk CoV,
152 Unk CoV,
152 Unk CoV,
153 Unk CoV,
153 Unk CoV,
154 Unk CoV,
154 Unk CoV,
155 Unk CoV,
155 Unk CoV,
156 Unk CoV,
156 Unk CoV,
157 Unk CoV,
157 Unk CoV,
158 Unk CoV,
158 Unk CoV,
159 Unk CoV,
159 Unk CoV,
160 Unk CoV,
160 Unk CoV,
161 Unk CoV,
161 Unk CoV,
323 162 SARS-CoV-1 RBD, SARS-CoV-1 Spike T rimer, SARS-CoV-2
RBD, SARS-CoV-2 Spike T rimer,
324 162 SARS-CoV-1 RBD, SARS-CoV-1 Spike T rimer, SARS-CoV-2
RBD, SARS-CoV-2 Spike T rimer,
325 163 Unk CoV,
326 163 Unk CoV,
327 164 Unk CoV,
328 164 Unk CoV,
329 165 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
330 165 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
331 166 Unk CoV,
332 166 Unk CoV,
333 167 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
334 167 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
335 168 Unk CoV,
336 168 Unk CoV,
337 169 Unk CoV,
338 169 Unk CoV,
339 170 Unk CoV,
340 170 Unk CoV,
341 171 SARS-CoV-2 Spike Trimer,
342 171 SARS-CoV-2 Spike Trimer,
343 172 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
344 172 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
345 173 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
346 173 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
347 174 Unk CoV,
348 174 Unk CoV,
349 175 Unk CoV,
350 175 Unk CoV,
351 176 Unk CoV,
352 176 Unk CoV,
353 177 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
354 177 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
355 178 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
356 178 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
357 179 SARS-CoV-1 RBD,
358 179 SARS-CoV-1 RBD,
359 180 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
360 180 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
361 181 Unk CoV,
362 181 Unk CoV,
363 182 Unk CoV,
364 182 Unk CoV,
365 183 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
366 183 SARS-CoV-1 RBD, SARS-CoV-1 Spike Trimer, SARS-CoV-2
RBD,
367 184 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
368 184 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
369 185 Unk CoV,
370 185 Unk CoV,
371 186 SARS-CoV-2 RBD, SARS-CoV-2 Spike T rimer,
372 186 SARS-CoV-2 RBD, SARS-CoV-2 Spike T rimer,
373 187 SARS-CoV-1 RBD, SARS-CoV-1 Spike T rimer, SARS-CoV-2
RBD,
374 187 SARS-CoV-1 RBD, SARS-CoV-1 Spike T rimer, SARS-CoV-2
RBD,
375 188 SARS-CoV-1 RBD,
376 188 SARS-CoV-1 RBD,
377 189 Unk CoV,
378 189 Unk CoV,
379 190 SARS-CoV-1 RBD,
380 190 SARS-CoV-1 RBD,
381 191 Unk CoV,
382 191 Unk CoV,
383 192 SARS-CoV-2 RBD,
384 192 SARS-CoV-2 RBD,
385 193 SARS-CoV-2 RBD,
386 193 SARS-CoV-2 RBD,
387 194 SARS-CoV-2 RBD,
388 194 SARS-CoV-2 RBD,
389 195 SARS-CoV-1 RBD, SARS-CoV-1 Spike T rimer, SARS-CoV-2
RBD,
390 195 SARS-CoV-1 RBD, SARS-CoV-1 Spike T rimer, SARS-CoV-2
RBD,
391 196 Unk CoV,
392 196 Unk CoV,
393 197 Unk CoV,
394 197 Unk CoV,
395 198 Unk CoV,
396 198 Unk CoV,
397 199 Unk CoV,
398 199 Unk CoV,
399 200 SARS-CoV-1 RBD,
400 200 SARS-CoV-1 RBD,
401 201 SARS-CoV-1 RBD,
402 201 SARS-CoV-1 RBD,
403 202 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid,
404 202 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid,
405 203 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid,
406 203 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid,
407 204 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid,
408 204 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid,
409 205 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid,
410 205 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid,
411 206 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid,
412 206 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid,
413 207 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid,
414 207 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid,
415 208 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid,
416 208 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid,
417 209 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid,
418 209 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid,
419 210 Unk CoV,
420 210 Unk CoV,
211 link CoV,
211 Unk CoV,
212 Unk CoV,
212 Unk CoV,
213 Unk CoV,
213 Unk CoV,
214 SARS-CoV-2 Nucleocapsid ,
214 SARS-CoV-2 Nucleocapsid ,
215 SARS-CoV-2 Nucleocapsid ,
215 SARS-CoV-2 Nucleocapsid ,
216 Unk CoV,
216 Unk CoV,
217 Unk CoV,
217 Unk CoV,
218 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
218 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
219 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
219 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
220 Unk CoV,
220 Unk CoV,
221 SARS-CoV-2 Nucleocapsid ,
221 SARS-CoV-2 Nucleocapsid ,
222 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
222 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
223 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
223 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
224 Unk CoV,
224 Unk CoV,
225 Unk CoV,
225 Unk CoV,
226 Unk CoV,
226 Unk CoV,
227 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
227 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
228 Unk CoV,
228 Unk CoV,
229 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
229 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
230 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
230 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
231 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
231 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
232 Unk CoV,
232 Unk CoV,
233 Unk CoV,
233 Unk CoV,
234 Unk CoV,
234 Unk CoV,
235 Unk CoV,
235 Unk CoV,
236 SARS-CoV-2 Nucleocapsid ,
236 SARS-CoV-2 Nucleocapsid ,
237 Unk CoV,
237 Unk CoV,
238 link CoV,
238 Unk CoV,
239 Unk CoV,
239 Unk CoV,
240 Unk CoV,
240 Unk CoV,
241 Unk CoV,
241 Unk CoV,
242 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
242 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
243 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
243 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
244 SARS-CoV-2 Membrane,
244 SARS-CoV-2 Membrane,
245 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
245 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
246 Unk CoV,
246 Unk CoV,
247 Unk CoV,
247 Unk CoV,
248 Unk CoV,
248 Unk CoV,
249 Unk CoV,
249 Unk CoV,
250 Unk CoV,
250 Unk CoV,
251 Unk CoV,
251 Unk CoV,
252 Unk CoV,
252 Unk CoV,
253 Unk CoV,
253 Unk CoV,
254 Unk CoV,
254 Unk CoV,
255 Unk CoV,
255 Unk CoV,
256 Unk CoV,
256 Unk CoV,
257 Unk CoV,
257 Unk CoV,
258 Unk CoV,
258 Unk CoV,
259 Unk CoV,
259 Unk CoV,
260 Unk CoV,
260 Unk CoV,
261 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
261 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
262 Unk CoV,
262 Unk CoV,
263 Unk CoV,
263 Unk CoV,
264 Unk CoV,
264 Unk CoV,
265 link CoV,
265 Unk CoV,
266 Unk CoV,
266 Unk CoV,
267 Unk CoV,
267 Unk CoV,
268 Unk CoV,
268 Unk CoV,
269 Unk CoV,
269 Unk CoV,
270 Unk CoV,
270 Unk CoV,
271 SARS-CoV-2 Nucleocapsid ,
271 SARS-CoV-2 Nucleocapsid ,
272 Unk CoV,
272 Unk CoV,
273 SARS-CoV-2 Virus ,
273 SARS-CoV-2 Virus ,
274 Unk CoV,
274 Unk CoV,
275 Unk CoV,
275 Unk CoV,
276 Unk CoV,
276 Unk CoV,
277 Unk CoV,
277 Unk CoV,
278 Unk CoV,
278 Unk CoV,
279 Unk CoV,
279 Unk CoV,
280 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
280 SARS-CoV-2 Membrane, SARS-CoV-2 Nucleocapsid ,
281 Unk CoV,
281 Unk CoV,
282 Unk CoV,
282 Unk CoV,
283 Unk CoV,
283 Unk CoV,
284 Unk CoV,
284 Unk CoV,
285 Unk CoV,
285 Unk CoV,
286 Unk CoV,
286 Unk CoV,
287 Unk CoV,
287 Unk CoV,
288 SARS-CoV-1 RBD , SARS-CoV-2 RBD ,
288 SARS-CoV-1 RBD , SARS-CoV-2 RBD ,
289 Unk CoV,
289 Unk CoV,
290 SARS-CoV-1 RBD ,
290 SARS-CoV-1 RBD ,
291 SARS-CoV-1 RBD ,
291 SARS-CoV-1 RBD ,
292 SARS-CoV-1 RBD,
292 SARS-CoV-1 RBD,
293 SARS-CoV-1 RBD,
293 SARS-CoV-1 RBD,
294 Unk CoV,
294 Unk CoV,
295 SARS-CoV-1 RBD,
295 SARS-CoV-1 RBD,
296 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
296 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
297 SARS-CoV-1 RBD,
297 SARS-CoV-1 RBD,
298 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
298 SARS-CoV-1 RBD, SARS-CoV-2 RBD,
299 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
299 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
300 Unk CoV,
300 Unk CoV,
301 Unk CoV,
301 Unk CoV,
302 Unk CoV,
302 Unk CoV,
303 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
303 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
304 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
304 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
305 Unk CoV,
305 Unk CoV,
306 Unk CoV,
306 Unk CoV,
307 Unk CoV,
307 Unk CoV,
308 Unk CoV,
308 Unk CoV,
309 HKUl-CoV S1+S2,
309 HKUl-CoV S1+S2,
310 HKUl-CoV S1+S2,
310 HKUl-CoV S1+S2,
311 Unk CoV,
311 Unk CoV,
312 Unk CoV,
312 Unk CoV,
313 SARS-CoV-2 RBD,
313 SARS-CoV-2 RBD,
314 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
314 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
315 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
315 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
316 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
316 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
317 Unk CoV,
317 Unk CoV,
318 Unk CoV,
318 Unk CoV,
319 HKUl-CoV S1+S2,
319 HKUl-CoV S1+S2,
320 HKUl-CoV S1+S2,
320 HKUl-CoV S1+S2,
321 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
321 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
322 SARS-CoV-2 RBD, SARS-CoV-1 SI,
322 SARS-CoV-2 RBD, SARS-CoV-1 SI,
323 SARS-CoV-2 RBD,
323 SARS-CoV-2 RBD,
324 link CoV,
324 link CoV,
325 link CoV,
325 link CoV,
326 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
326 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
327 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
327 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
328 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
328 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
329 link CoV,
329 link CoV,
330 link CoV,
330 link CoV,
331 link CoV,
331 link CoV,
332 SARS-CoV-2 RBD,
332 SARS-CoV-2 RBD,
333 link CoV,
333 link CoV,
334 SARS-CoV-2 RBD,HKUl-CoV S1+S2,
334 SARS-CoV-2 RBD,HKUl-CoV S1+S2,
335 link CoV,
335 link CoV,
336 link CoV,
336 link CoV,
337 SARS-CoV-2 RBD, SARS-CoV-1 SI,
337 SARS-CoV-2 RBD, SARS-CoV-1 SI,
338 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
338 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
339 HKUl-CoV S1+S2,
339 HKUl-CoV S1+S2,
340 HKUl-CoV S1+S2,
340 HKUl-CoV S1+S2,
341 link CoV,
341 link CoV,
342 link CoV,
342 link CoV,
343 link CoV,
343 link CoV,
344 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
344 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
345 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
345 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
691 346 link CoV,
692 346 Unk CoV,
693 347 SARS-CoV-2 RBD,HKUl-CoV S1+S2,
694 347 SARS-CoV-2 RBD,HKUl-CoV S1+S2,
695 348 Unk CoV,
696 348 Unk CoV,
697 349 Unk CoV,
698 349 Unk CoV,
699 350 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
700 350 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
701 351 Unk CoV,
702 351 Unk CoV,
703 352 Unk CoV,
704 352 Unk CoV,
705 353 Unk CoV,
706 353 Unk CoV,
707 354 Unk CoV,
708 354 Unk CoV,
709 355 SARS-CoV-2 RBD, SARS-CoV-2 Virus , HKUl-CoV S1+S2,SARS-
CoV-1 Sl,
710 355 SARS-CoV-2 RBD, SARS-CoV-2 Virus , HKUl-CoV S1+S2,SARS-
CoV-1 Sl,
711 356 SARS-CoV-2 RBD, SARS-CoV-2 Virus , HKUl-CoV S1+S2,SARS-
CoV-1 Sl,
712 356 SARS-CoV-2 RBD, SARS-CoV-2 Virus , HKUl-CoV S1+S2,SARS-
CoV-1 Sl,
713 357 HKUl-CoV S1+S2,
714 357 HKUl-CoV S1+S2,
715 358 SARS-CoV-2 RBD,HKUl-CoV S1+S2,
716 358 SARS-CoV-2 RBD,HKUl-CoV S1+S2,
717 359 SARS-CoV-2 RBD,HKUl-CoV S1+S2,
718 359 SARS-CoV-2 RBD,HKUl-CoV S1+S2,
719 360 SARS-CoV-2 RBD,HKUl-CoV S1+S2,
720 360 SARS-CoV-2 RBD,HKUl-CoV S1+S2,
721 361 Unk CoV,
722 361 Unk CoV,
723 362 Unk CoV,
724 362 Unk CoV,
725 363 Unk CoV,
726 363 Unk CoV,
727 364 Unk CoV,
728 364 Unk CoV,
729 365 Unk CoV,
730 365 Unk CoV,
731 366 Unk CoV,
732 366 Unk CoV,
733 367 Unk CoV,
734 367 Unk CoV,
735 368 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
736 368 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
737 369 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
738 369 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
739 370 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
740 370 SARS-CoV-2 RBD,HKUl-CoV S1+S2, SARS-CoV-1 SI,
371 link CoV,
371 Unk CoV,
372 Unk CoV,
372 Unk CoV,
373 Unk CoV,
373 Unk CoV,
374 Unk CoV,
374 Unk CoV,
375 HKUl-CoV S1+S2,
375 HKUl-CoV S1+S2,
376 HKUl-CoV S1+S2,
376 HKUl-CoV S1+S2,
377 HKUl-CoV S1+S2,
377 HKUl-CoV S1+S2,
378 SARS-CoV-2 RBD,HKUl-CoV S1+S2,
378 SARS-CoV-2 RBD,HKUl-CoV S1+S2,
379 SARS-CoV-2 RBD,HKUl-CoV S1+S2,
379 SARS-CoV-2 RBD,HKUl-CoV S1+S2,
380 SARS-CoV-2 RBD,HKUl-CoV S1+S2,
380 SARS-CoV-2 RBD,HKUl-CoV S1+S2,
381 Unk CoV,
381 Unk CoV,
382 Unk CoV,
382 Unk CoV,
383 Unk CoV,
383 Unk CoV,
384 Unk CoV,
384 Unk CoV,
385 Unk CoV,
385 Unk CoV,
386 Unk CoV,
386 Unk CoV,
387 Unk CoV,
387 Unk CoV,
388 Unk CoV,
388 Unk CoV,
389 Unk CoV,
389 Unk CoV,
390 Unk CoV,
390 Unk CoV,
391 HKUl-CoV S1+S2, SARS-CoV-1 SI,
391 HKUl-CoV S1+S2, SARS-CoV-1 SI,
392 HKUl-CoV S1+S2, SARS-CoV-1 SI,
392 HKUl-CoV S1+S2, SARS-CoV-1 SI,
393 HKUl-CoV S1+S2, SARS-CoV-1 SI,
393 HKUl-CoV S1+S2, SARS-CoV-1 SI,
394 Unk CoV,
394 Unk CoV,
395 Unk CoV,
395 Unk CoV,
396 Unk CoV,
396 Unk CoV,
397 Unk CoV,
397 Unk CoV,
398 Unk CoV, 398 link CoV, 399 Unk CoV, 399 Unk CoV, 400 Unk CoV, 400 Unk CoV, 401 Unk CoV, 401 Unk CoV, 402 Unk CoV, 402 Unk CoV,
Claims
1. A method comprising the steps of: finding a subject needing treatment from a SARS-CoV - 2; and administering a therapeutically effective amount of an anti-SARS-CoV-2 antibody selected from Table I or Table 2 to the subject.
2. The method of claim I, wherein the anti-SARS-CoV-2 antibody is produced recombinantly.
3. The method of claim 1, wherein the anti-SARS-COV-2 antibody is an antibody fragment.
4. The method of claim 1 , wherein the anti-SARS-CoV-2 antibody binds to a SARS-CoV-2 receptor binding domain.
5. The method of claim 1, wherein the anti-SARS-CoV-2 antibody binds to a SARS-CoV-2 receptor binding domain.
6. The method of claim 1, wherein the anti-SARS-CoV-2 antibody binds to a SARS-CoV-2
51 protein.
7. The method of claim 1, wherein the wherein the anti-SARS-CoV-2 antibody binds to a SARS-CoV-2 SI protein.
8. The method of claim 1, wherein the anti-SARS-CoV-2 antibody binds to a SARS-CoV-2
52 protein.
9. The method of claim 1, wherein the subject is infected with the SARS-CoV-2.
10. The method of claim 1, wherein the anti-SARS-CoV-2 antibody is given to the subject prophylactically.
11. An anti-SARS-CoV-2 antibody, comprising an antibody selected from Table 1 or Table 2.
12. The anti-SzARS-CoV-2 antibody of claim 11, wherein the anti-SARS-CoV-2 antibody is produced recombinantly .
13. The anti-SARS-CoV-2 antibody of claim 11, wherein the anti-SARS-COV-2 antibody is an antibody fragment.
14. The anti-SARS-CoV-2 antibody of claim 11, wherein the anti-SARS-CoV-2 antibody binds to a SARS-CoV-2 receptor binding domain.
15. The anti-SARS-CoV-2 antibody of claim 11, wherein the anti-SARS-CoV-2 antibody binds to a SARS-CoV-2 receptor binding domain.
16. The anti-SARS-CoV-2 antibody of claim 1 1, wherein the anti-SARS-CoV-2 antibody binds to a S/\RS-CoV-2 SI protein.
17. The anti-SARS-CoV-2 antibody of claim 11, wherein the wherein the anti-SARS-CoV-2 antibody binds to a SARS-CoV-2 SI protein.
18. The anti-SARS-CoV-2 antibody of claim 11, wherein the anti-SARS-CoV-2 antibody binds to a SARS-CoV-2 S2 protein.
19. A pharmaceutical composition, comprising an antibody of any one of claims 11-18 and an excipient.
20. The composition of claim 19, wherein the pharmaceutical composition is formulated for administration by inhalation.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202163253677P | 2021-10-08 | 2021-10-08 | |
US63/253,677 | 2021-10-08 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2023064717A2 true WO2023064717A2 (en) | 2023-04-20 |
WO2023064717A3 WO2023064717A3 (en) | 2023-09-14 |
Family
ID=85988855
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2022/077810 WO2023064717A2 (en) | 2021-10-08 | 2022-10-07 | Antibodies for sars-cov-2 and uses thereof |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2023064717A2 (en) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10822379B1 (en) * | 2020-03-12 | 2020-11-03 | University of Pittsburgh—of the Commonwealth System of Higher Education | Molecules that bind to SARS-CoV-2 |
US11365239B2 (en) * | 2020-03-20 | 2022-06-21 | Tsb Therapeutics (Beijing) Co., Ltd. | Anti-SARS-COV-2 antibodies and uses thereof |
WO2021195326A1 (en) * | 2020-03-26 | 2021-09-30 | Vanderbilt University | Human monoclonal antibodies to severe acute respiratory syndrome coronavirus 2 (sars-cov-2) |
SG11202103404PA (en) * | 2020-04-02 | 2021-04-29 | Regeneron Pharma | Anti-sars-cov-2-spike glycoprotein antibodies and antigen-binding fragments |
WO2021231237A2 (en) * | 2020-05-11 | 2021-11-18 | Augmenta Bioworks, Inc. | Antibodies for sars-cov-2 and uses thereof |
-
2022
- 2022-10-07 WO PCT/US2022/077810 patent/WO2023064717A2/en unknown
Also Published As
Publication number | Publication date |
---|---|
WO2023064717A3 (en) | 2023-09-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11919944B2 (en) | Antibodies for SARS-CoV-2 and uses thereof | |
JP7328267B2 (en) | Trispecific and/or trivalent binding proteins for prevention or treatment of HIV infection | |
US11692031B2 (en) | Antibody constructs for CLDN18.2 and CD3 | |
WO2019179366A1 (en) | Novel anti-cd47 antibodies | |
JP6811723B2 (en) | Multivalent human immunodeficiency virus antigen-binding molecule and its usage | |
US10858649B2 (en) | Immune repertoire sequence amplification methods and applications | |
CN113166254A (en) | Trispecific anti-CD 38, anti-CD 28, and anti-CD 3 binding proteins and methods of use for treating viral infections | |
US20210388105A1 (en) | Novel anti-cd39 antibodies | |
EP2692737A1 (en) | Fully human anti-vap-1 monoclonal antibodies | |
KR20220003055A (en) | Recombinant polyclonal proteins and methods of use thereof | |
US10647754B2 (en) | Stabilized single human CD4 domains and fusion proteins | |
US20230293652A1 (en) | Immunostimulatory adjuvants | |
CN106565840B (en) | Antibody against hepatitis B surface antigen and use thereof | |
CN113480641B (en) | Antibodies for the treatment of hepatitis B infections and related diseases | |
JP2023538369A (en) | Anti-CD73 antibody and its use | |
WO2014085580A1 (en) | Methods and compositions involving a flu vaccine | |
WO2023064717A2 (en) | Antibodies for sars-cov-2 and uses thereof | |
CN114829385A (en) | Bifunctional molecules comprising IL-7 variants | |
CN106892979B (en) | Fully human neutralizing antibody against H7N9 virus | |
WO2022150740A1 (en) | Cross-reactive antibodies recognizing the coronavirus spike s2 domain | |
RU2812910C2 (en) | Antibodies to cd38 and combinations with antibodies to cd3 and cd28 | |
JP3364181B2 (en) | Human immunodeficiency virus envelope polypeptide and its antibody | |
CN117279947A (en) | Antigen binding molecules targeting CD20 and CD22 for use in proliferative diseases | |
WO2023108117A2 (en) | Engineered fc domains and engineered hcmv viral fc receptors | |
CN102727889A (en) | Application of specific antibodies in preparation of biological products for controlling virus infection based on virus acceptor binding site selection |