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Epitope analogs

a technology of epitopes and analogs, applied in the field of epitope analogs, can solve the problems of cells that do not respond to free or soluble antigens, and achieve the effect of similar or improving immunological properties

Inactive Publication Date: 2006-03-16
MANNKIND CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes analogs of a specific T cell epitope, which can be used to stimulate the immune system. These analogs can have improved properties compared to the original epitope. The patent also includes nucleic acids that can express these analogs. Overall, the invention provides new tools for research and potential therapies for cancer and other diseases.

Problems solved by technology

The patent text discusses the role of MHC proteins in T cell recognition of antigens. The technical problem addressed is the requirement for MHC proteins to present antigens to T cells in order for them to recognize and respond to the antigen signal.

Method used

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Examples

Experimental program
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Effect test

example 1

Peptide Synthesis, Purification and Characterization

[0361] Peptides were synthesized on either a Symphony multiple peptide synthesizer (PTI technologies, MA) or an ABI 433A peptide synthesizer (Applied Biosystems, Foster City, Calif.) at 0.05-0.1 mmole scale using standard Fmoc solid phase chemistry. C-terminal free acid peptides were synthesized using pre-load PEG-PS resins (on Symphony) or Wang resin (on ABI). C-terminal amidated peptides were synthesized on Fmoc-PAL-PEG-PS resin. All resins were purchased from Applied Biosystems (Foster City, Calif.). The Fmoc-amino acids used in peptide syntheses were purchased from Novabiochem (San Diego, Calif.) and AnaSpec (San Jose, Calif.). Post-synthesis cleavage was carried on by the standard protocol.

[0362] Peptide purification was carried out on either semi-preparative HPLC columns or SPE cartridges (Phenomenex, Torrance, Calif.). The purity of all peptides was ≧90%. The identity of each peptide was verified by Maldi-TOF MS (Voyager D...

example 2

De Novo Designed SSX-241-49 Analogs

[0363] Structural modification of a moderately antigenic peptide can considerably improve peptide-MHC binding, CTL recognition, and / or immunogenicity. General guidelines regarding how to modify a wild-type epitope in order to achieve a peptide analog with enhanced potency are known in the art. An appreciated strategy is to optimize the residues at the so-called anchor positions for binding to the particular MHC molecule at issue. In the case of HLA-A2 a marked preference for hydrophobic residues at the P2 and PΩ positions has been observed, particularly L, and M at P2, and V at PΩ. (PΩ denotes the C-terminal residue of the epitope. For HLA-A2 that is P9 or P10 depending on the length of the peptide.) Replacing the P1 position with aromatic residues, such as F, Y and W can also be advantageous.

TABLE 7Coefficients used by the BIMAS algorithm(Algorithm available by hypertext transfer protocol: / / bimas.cit.nih.gov / molbio / hla_bind / )9-mer Coefficient T...

example 3

[0366] The following analogs were produced using the predictions in Example 1.

TABLE 9SEQ IDCatergoryNumberPeptide nameSequencewild-type1SSX-2 41-49KASEKIFYVN-terminal Primary Anchor2SSX-2 41-49 (A42L)KLSEKIFYV3SSX-2 41-49 (A42V)KVSEKIFYV4SSX-2 41-49 (A42I)KISEKIFYV5SSX-2 41-49 (A42M)KMSEKIFYV6SSX-2 41-49 (A42(D-Ala))K(D-Ala)SEKIFYV7SSX-2 41-49 (A42(D-Leu))K(D-Leu)SEKIFYV8SSX-2 41-49 (A42(D-Val))K(D-Val)SEKIFYV9SSX-2 41-49 (A42(Nal-1))KNal-1SEKIFYV10SSX-2 41-49 (A42(Nal-2))KNal-2SEKIFYV11SSX-2 41-49 (A42(Abu))KAbuSEKIFYV12SSX-2 41-49 (A42(Nle))KNleSEKIFYV13SSX-2 41-49 (A42(Nva))KNvaSEKIFYV14SSX-2 41-49 (A42(Aib))KAibSEKIFYVN-terminal Secondary15SSX-2 41-49 (K41F)FASEKIFYVAnchor16SSX-2 41-49 (K41W)WASEKIFYV17SSX-2 41-49 (K41Y)YASEKIFYV18SSX-2 41-49 (K41(D-Lys))(D-Lys)ASEKIFYV19SSX-2 41-49 (K41(Phg))PhgASEKIFYV20SSX-2 41-49 (K41(Cha))ChaASEKIFYV21SSX-2 41-49 (K41(Phe-4F))Phe(4-F)ASEKIFYV22SSX-2 41-49 (K41(Phe-4NO2))Phe(4-NO2)ASEKIFYV23SSX-2 41-49 (K41(O-methyl Tyr))O-methyl-TyrASEKIF...

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Abstract

Some embodiments relate to analogs of peptides corresponding to class I MHC-restricted T cell epitopes and methods for their generation. These analogs can contain amino acid substitutions at residues that directly interact with MHC molecules, and can confer improved, modified or useful immunologic properties. Additionally classes of analogs, in which the various substitutions comprise the non-standard residues norleucine and/or norvaline, are disclosed.

Description

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Claims

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Application Information

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Owner MANNKIND CORP
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