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Polypeptide-antigen conjugates with non-natural amino acids

A technology of unnatural amino acids and conjugates, applied in the field of polypeptide-antigen conjugates with unnatural amino acids

Pending Publication Date: 2019-10-22
VAXCYTE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this strategy suffers from the inconvenient fact that not every macromolecule elicits a strong immune response

Method used

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  • Polypeptide-antigen conjugates with non-natural amino acids
  • Polypeptide-antigen conjugates with non-natural amino acids
  • Polypeptide-antigen conjugates with non-natural amino acids

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0506] Example 1: Synthesis of single site eCRM fractions K11TAG, K25TAG, K34TAG, K38TAG, K40TAG, K52TAG, K60TAG, K77TAG, K83TAG, K91TAG, K96TAG and K103TAG

[0507] eCRM was expressed in cell-free protein synthesis (CFPS) extracts provided by Sutro Biopharma, Inc. (South San Francisco, Calif.). The characterization and preparation of such extracts are described in other publications; in this case, the extracts are usually as described in Zawada et al., 2011, "Biotechnol. Bioeng.", 108(7) , 1570-1578, using the following modifications from US2016 / 0257946: (1) Cell-free extracts were prepared from outer membrane protein T-sensitive RF-1 attenuated strains engineered to to overexpress E. coli DsbC; (2) prepare cell-free extracts from a similar RF-1 attenuated E. coli strain engineered to produce an orthogonal CUA-encoding tRNA for insertion at the amber stop codon Unnatural amino acids; (3) the cell-free extracts from (1) and (2) were mixed (85:15 ratio) and treated with 50 μM ...

example 2

[0514] Example 2: Design of multiple nnAA eCRMs

[0515] Multiple nnAA eCRM variants were selected as described in the detailed description above. Variants were synthesized by CFPS and tested as in Example 1.

[0516] Table 2: Various nnAA eCRM variants

[0517] Variants# K25 K34 K38 K40 K213 K215 K228 K245 K265 K386 K523 K527 1 √ √ √ √ √ √ 2 √ √ √ √ √ √ 3 √ √ √ √ √ √ 4 √ √ √ √ √ √ 5 √ √ √ √ √ √ 6 √ √ √ √ √ √ 7 √ √ √ √ √ √ 8 √ √ √ √ √ √ 9 √ √ √ √ √ √ 10 √ √ √ √ √ √ 11 √ √ √ √ √ √ 12 √ √ √ √ √ √ 13 √ √ √ √ √ √ 14 √ √ √ √ √ √ 15 √ √ √ √ √ √ 16 √ √ √ √ √ √ 17 √ √ √ √ √ √ 18 √ √ ...

example 3

[0524] Example 3: Identification of T cell epitopes in Pfs25

[0525] According to the method described in Diethelm-Okita et al., " Journal of Infectious Diseases (J Infect Dis.) " 1997 February; 175 (2): 382-91, T Cell activation epitopes. Briefly, a peptide fragment consisting of 20 amino acids and overlapping by 5 amino acids was synthesized corresponding to the complete expression sequence of Pfs25. CD8+-depleted and CD4+-enriched human peripheral blood lymphocytes (PBL) were obtained from multiple subjects. PBLs were plated in triplicate and incubated with individual synthetic peptides spanning the sequence of Pfs25 serving as experimental stimuli. By having [ 3 Cultures of [H]-thymidine were pulsed to measure PBL proliferation in response to each peptide fragment and compared across cultures derived from different individuals. Fragments of Pfs25 that stimulate proliferation were identified as including T cell epitopes. Fragments that stimulated PBL proliferation fro...

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Abstract

Methods for the production of immunogenic compositions containing a non-natural amino acid are disclosed. The non-natural amino acid can be a site for attachment of antigens, such as bacterial capsular polysaccharides, to make immunogenic conjugates. Bio-orthogonal attachment chemistry incorporated into the non-natural amino acids allows for more efficient and potent antigen presentation to the immune system, simplified purification, and more well-defined structure of these semi-synthetic immunogens.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Patent Application 62 / 441,115, filed December 30, 2016, U.S. Provisional Patent Application 62 / 530,803, filed July 10, 2017, U.S. Provisional Patent Application, filed October 4, 2017 62 / 568,201 and U.S. Provisional Patent Application 62 / 591,160, filed November 27, 2017, each of which is incorporated herein by reference. Background technique [0003] Vaccines based on isolated antigenic macromolecules (e.g., first-generation meningococcal, pneumococcal, and Haemophilus polysaccharide vaccines) represent a significant advantage over earlier vaccine formulations based on attenuated live vaccines or inactivated organism vaccines. Improve. [0004] Purified macromolecules are significantly easier to manufacture, have improved safety profiles, and can generate more effective specific immune responses (eg, purified macromolecules can target antigens that are more conserved or importan...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/09A61P31/04A61K47/64
CPCA61K39/092A61K2039/6037A61K47/6415A61K47/646A61P31/04A61P37/00A61P29/00A61K39/385C07K17/02A61K2039/627A61K2039/70A61K2039/575
Inventor J·费尔曼J·海因里希斯W·陈
Owner VAXCYTE INC
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