Certain peptide analogs that carry substitutions at residues other than the main major histocompatibility complex anchors and are surprisingly much more antigenic than wild-type peptide (heteroclitic analogs). To date, it was unknown how frequently wild-type epitopes could be modified to obtain heteroclitic activity. In this study, we analyzed a large panel of analogs of two different human histocompatibility leukocyte antigen (HLA)-A2.1–restricted epitopes and found that heteroclitic analogs were associated with higher magnitude responses and increased (up to 107-fold) sensitivity to antigen, and corresponded to conservative or semiconservative substitutions at odd-numbered positions in the middle of the peptide (positions 3, 5, or 7). These findings were validated by performing additional immunogenicity studies in murine and human systems with four additional epitopes. The biological relevance of heteroclitic analogs was underlined when predicted analogs of the p53.261 epitope was shown to induce cytotoxic T lymphocytes (CTLs) that recognize low concentrations of peptide (high avidity) in vivo and demonstrate in vitro antitumor recognition. Finally, in vitro immunization of human peripheral blood mononuclear cells with two heteroclitic analogs resulted in recruitment of more numerous CTLs which were associated with increased antigen sensitivity. In conclusion, heteroclitic analogs were identified in each of the six cases studied and structural features were defined which allow identification of such analogs. The strong CTL immunity elicited by heteroclitic epitopes suggest that they could be of significant value in vaccination against tolerant or weakly immunogenic tumor-associated and viral antigens.
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17 September 2001
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September 17 2001
Structural Features of Peptide Analogs of Human Histocompatibility Leukocyte Antigen Class I Epitopes That Are More Potent and Immunogenic than Wild-Type Peptide
Shabnam Tangri,
Shabnam Tangri
aEpimmune Incorporated, San Diego, CA 92121
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Glenn Y. Ishioka,
Glenn Y. Ishioka
aEpimmune Incorporated, San Diego, CA 92121
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Xiuqing Huang,
Xiuqing Huang
aEpimmune Incorporated, San Diego, CA 92121
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John Sidney,
John Sidney
aEpimmune Incorporated, San Diego, CA 92121
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Scott Southwood,
Scott Southwood
aEpimmune Incorporated, San Diego, CA 92121
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John Fikes,
John Fikes
aEpimmune Incorporated, San Diego, CA 92121
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Alessandro Sette
Alessandro Sette
aEpimmune Incorporated, San Diego, CA 92121
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Shabnam Tangri
aEpimmune Incorporated, San Diego, CA 92121
Glenn Y. Ishioka
aEpimmune Incorporated, San Diego, CA 92121
Xiuqing Huang
aEpimmune Incorporated, San Diego, CA 92121
John Sidney
aEpimmune Incorporated, San Diego, CA 92121
Scott Southwood
aEpimmune Incorporated, San Diego, CA 92121
John Fikes
aEpimmune Incorporated, San Diego, CA 92121
Alessandro Sette
aEpimmune Incorporated, San Diego, CA 92121
Abbreviations used in this paper: CEA, carcinoembryonic antigen; HBV, hepatitis B virus; ELISPOT, enzyme-linked immunospot.
Received:
April 25 2001
Revision Requested:
June 28 2001
Accepted:
July 18 2001
Online ISSN: 1540-9538
Print ISSN: 0022-1007
© 2001 The Rockefeller University Press
2001
The Rockefeller University Press
J Exp Med (2001) 194 (6): 833–846.
Article history
Received:
April 25 2001
Revision Requested:
June 28 2001
Accepted:
July 18 2001
Citation
Shabnam Tangri, Glenn Y. Ishioka, Xiuqing Huang, John Sidney, Scott Southwood, John Fikes, Alessandro Sette; Structural Features of Peptide Analogs of Human Histocompatibility Leukocyte Antigen Class I Epitopes That Are More Potent and Immunogenic than Wild-Type Peptide. J Exp Med 17 September 2001; 194 (6): 833–846. doi: https://doi.org/10.1084/jem.194.6.833
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