US 2025/0090650 A1Published application

Modified influenza b hemagglutinin polypeptides and nucleic acids and uses thereof

AssigneeSanofi

InventorsChristine BRICAULT, Gwo-Yu CHUANG, Raul GOMILA, Ching-Lin HSIEH, Andreas KARLSSON

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Abstract

This application relates to modified influenza B hemagglutinin polypeptides and nucleic acids, such as messenger ribonucleic acids (mRNAs), encoding the same, as well as compositions comprising the same, vaccines comprising the same, and methods of using the same, such as in the prevention and/or treatment of diseases or conditions caused by influenza B viruses.

Claims45

Dependent claims

An artificial messenger ribonucleic acid (mRNA) encoding an influenza B HA polypeptide, wherein the influenza B HA polypeptide comprises:

a) at least one proline substitution relative to a corresponding wild-type influenza B HA polypeptide, wherein the at least one proline substitution is at amino acid position 363, 366, 371, 372, 376, 380, 383, 390, 391, 393, 395, 397, 399, 421, 430, 431, 434, 436, and/or 490 as indexed by reference to the amino acid sequence of SEQ ID NO:
1;
b) at least two cysteine substitutions relative to a corresponding wild-type influenza B HA polypeptide, wherein the at least two cysteine substitutions are at amino acid positions 20 and 387, 35 and 408, 36 and 415, 37 and 411, 125 and 431, 127 and 431, 185 and 223, 186 and 224, 186 and 239, 188 and 241, 232 and 433, 233 and 434, 239 and 276, 346 and 465, 367 and 478, 378 and 397, 380 and 397, 383 and 401, 387 and 510, 394 and 507, 394 and 510, 396 and 510, 396 and 514, 401 and 475, 430 and 437, 430 and 438, and/or 430 and 439, as indexed by reference to the amino acid sequence of SEQ ID NO:
1;
c) at least one cavity filling amino acid substitution relative to a corresponding wild-type influenza B HA polypeptide, wherein the at least one cavity filling amino acid substitution is at amino acid position 460, 467, and/or 474 as indexed by reference to the amino acid sequence of SEQ ID NO:
1;
d) one or more interface stabilization amino acid substitutions relative to a corresponding wild-type influenza B HA polypeptide, wherein the one or more interface stabilization amino acid substitutions are at amino acid position 18, 121, 188, 226, 228, 408, 435, and/or 460 as indexed by reference to the amino acid sequence of SEQ ID NO:
1;
e) one or more pH sensor knock-out amino acid substitutions relative to a corresponding wild-type influenza B HA polypeptide, wherein the one or more pH sensor knock-out amino acid substitutions are at amino acid position 226, 228, 237, 239, 383, 388, 391, 401, 405, 408, 435, 460, 474 and/or 475 as indexed by reference to the amino acid sequence of SEQ ID NO:
1;
f) at least one amino acid substitution relative to a corresponding wild-type influenza B HA polypeptide, wherein the at least one amino acid substitution generates or disrupts a N-linked glycosylation motif in the influenza B HA polypeptide and is at amino acid position 28, 60, 62, 141, 143, 186, 187, 214, 216, 223, 224, 336, and/or 349 as indexed by reference to the amino acid sequence of SEQ ID NO:
1;
and/or
g) at least one amino acid substitution relative to a corresponding wild-type influenza B HA polypeptide, wherein the at least one amino acid substitution is at amino acid position 157, 177, 218, and/or 257 as indexed by reference to the amino acid sequence of SEQ ID NO:
1.

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Dependencies are inferred from the claim text.

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Abstract

An artificial messenger ribonucleic acid (mRNA) encoding an influenza B HA polypeptide, wherein the influenza B HA polypeptide comprises:

a) at least one proline substitution relative to a corresponding wild-type influenza B HA polypeptide, wherein the at least one proline substitution is at amino acid position 363, 366, 371, 372, 376, 380, 383, 390, 391, 393, 395, 397, 399, 421, 430, 431, 434, 436, and/or 490 as indexed by reference to the amino acid sequence of SEQ ID NO:
1;
b) at least two cysteine substitutions relative to a corresponding wild-type influenza B HA polypeptide, wherein the at least two cysteine substitutions are at amino acid positions 20 and 387, 35 and 408, 36 and 415, 37 and 411, 125 and 431, 127 and 431, 185 and 223, 186 and 224, 186 and 239, 188 and 241, 232 and 433, 233 and 434, 239 and 276, 346 and 465, 367 and 478, 378 and 397, 380 and 397, 383 and 401, 387 and 510, 394 and 507, 394 and 510, 396 and 510, 396 and 514, 401 and 475, 430 and 437, 430 and 438, and/or 430 and 439, as indexed by reference to the amino acid sequence of SEQ ID NO:
1;
c) at least one cavity filling amino acid substitution relative to a corresponding wild-type influenza B HA polypeptide, wherein the at least one cavity filling amino acid substitution is at amino acid position 460, 467, and/or 474 as indexed by reference to the amino acid sequence of SEQ ID NO:
1;
d) one or more interface stabilization amino acid substitutions relative to a corresponding wild-type influenza B HA polypeptide, wherein the one or more interface stabilization amino acid substitutions are at amino acid position 18, 121, 188, 226, 228, 408, 435, and/or 460 as indexed by reference to the amino acid sequence of SEQ ID NO:
1;
e) one or more pH sensor knock-out amino acid substitutions relative to a corresponding wild-type influenza B HA polypeptide, wherein the one or more pH sensor knock-out amino acid substitutions are at amino acid position 226, 228, 237, 239, 383, 388, 391, 401, 405, 408, 435, 460, 474 and/or 475 as indexed by reference to the amino acid sequence of SEQ ID NO:
1;
f) at least one amino acid substitution relative to a corresponding wild-type influenza B HA polypeptide, wherein the at least one amino acid substitution generates or disrupts a N-linked glycosylation motif in the influenza B HA polypeptide and is at amino acid position 28, 60, 62, 141, 143, 186, 187, 214, 216, 223, 224, 336, and/or 349 as indexed by reference to the amino acid sequence of SEQ ID NO:
1;
and/or
g) at least one amino acid substitution relative to a corresponding wild-type influenza B HA polypeptide, wherein the at least one amino acid substitution is at amino acid position 157, 177, 218, and/or 257 as indexed by reference to the amino acid sequence of SEQ ID NO:
1.

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