Human population-based identification of CD4+ T-cell peptide epitope determinants

Stickler, Marcia; Chin, R; Faravashi, Nargol; Gebel, Wendy; Razo, O. Jennifer; Rochanayon, Narapon; Power, Scott D.; Valdes, Ana M.; Holmes, Susan; Harding, Fiona

doi:10.1016/s0022-1759(03)00279-5

Cited by 15 publications

(16 citation statements)

References 45 publications

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“…The average percent response for all the peptides tested was 4.04 F 2.86. This background rate is low, consistent with a lack of donor preexposure to h-lactamase (19).…”

Section: Cd4mentioning

confidence: 64%

“…+ T-Cell Epitopes CD4 + T-cell peptide epitope determinants were identified using community donor blood as described (19). Briefly, dendritic cells were differentiated in vitro from adherent monocytes.…”

Section: Determination Of Cd4mentioning

confidence: 99%

“…The percentage of donors responding to each peptide is reported. Epitope designations were determined as described previously (19). HLA-DRB1 and HLA-DQB1 alleles were determined for each donor using a commercially available kit (Dynal, Brown Deer, WI).…”

Section: Determination Of Cd4mentioning

confidence: 99%

“…Using a variety of techniques to localize and eliminate CD4 + T-cell epitopes, several groups have published reports on reduced immunogenicity of therapeutic proteins (35,36,24). The functional method used here allows for the characterization of immunodominant CD4 + T-cell epitope responses on a human population basis (19,37). Elimination of immunodominant responses has been shown to reduce responses to subdominant CD4 + T-cell epitopes in both epitope spreading and direct priming responses (38,24).…”

Section: T-cell Epitopes Are Critical For Immune Responsementioning

confidence: 99%

“…h-Lactamase from Enterobacter cloacae was selected as the starting enzyme, as it has been shown to activate prodrugs based on multiple commonly used chemotherapeutic agents. The amino acid sequence of h-lactamase was assessed for the presence of CD4 + T-cell epitopes using an in vitro assay (19). Subsequently, several CD4 + T-cell epitopes from the h-lactamase sequence were modified to reduce its immunogenic potential while retaining sufficient protein expression and stability to preserve the utility of the enzyme for use in ADEPT.…”

Section: Introductionmentioning

confidence: 99%

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A β-lactamase with reduced immunogenicity for the targeted delivery of chemotherapeutics using antibody-directed enzyme prodrug therapy

Harding¹,

Liu²,

Stickler³

et al. 2005

Molecular Cancer Therapeutics

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Antibody-directed enzyme prodrug therapy (ADEPT) delivers chemotherapeutic agents in high concentration to tumor tissue while minimizing systemic drug exposure. B-Lactamases are particularly useful enzymes for ADEPT systems due to their unique substrate specificity that allows the activation of a variety of lactam-based prodrugs with minimal interference from mammalian enzymes. We evaluated the amino acid sequence of B-lactamase from Enterobacter cloacae for the presence of human T-cell epitopes using a cell-based proliferation assay using samples from 65 community donors. We observed a low background response that is consistent with a lack of preexposure to this enzyme. B-Lactamase was found to contain four CD4 + T-cell epitopes. For two of these epitopes, we identified single amino acid changes that result in significantly reduced proliferative responses while retaining stability and activity of the enzyme. The B-lactamase variant containing both changes induces significantly less proliferation in human and mouse cell assays, and 5-fold lower levels of IgG1 in mice were observed after repeat administration of B-lactamase variant with adjuvant. The B-lactamase variant should be very suitable for the construction of ADEPT fusion proteins, as it combines high activity toward lactam prodrugs, high plasma stability, a monomeric architecture, and a relatively low risk of eliciting an immune response in patients. [Mol Cancer Ther 2005;4(11):1791-800]

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“…The average percent response for all the peptides tested was 4.04 F 2.86. This background rate is low, consistent with a lack of donor preexposure to h-lactamase (19).…”

Section: Cd4mentioning

confidence: 64%

Section: Determination Of Cd4mentioning

confidence: 99%

Section: Determination Of Cd4mentioning

confidence: 99%

Section: T-cell Epitopes Are Critical For Immune Responsementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A β-lactamase with reduced immunogenicity for the targeted delivery of chemotherapeutics using antibody-directed enzyme prodrug therapy

Harding¹,

Liu²,

Stickler³

et al. 2005

Molecular Cancer Therapeutics

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View full text Add to dashboard Cite

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Development of a Human Antibody Tolerant Mouse Model to Assess the Immunogenicity Risk Due to Aggregated Biotherapeutics

Jawa

Joubert

et al. 2013

Journal of Pharmaceutical Sciences

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T‐Cell epitope discovery for variola and vaccinia viruses

Kennedy

2006

Reviews in Medical Virology

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Variola major, the causative agent of smallpox, afflicted mankind throughout history until the worldwide World Health Organisation WHO vaccination campaign successfully eradicated the disease. Unfortunately, recent concerns about bioterrorism have renewed scientific interest in this virus. One essential component of our biodefense and preparedness efforts is an understanding of poxvirus immunity. To this end a number of laboratories have sought to discover T- and B-Cell epitopes from select agents such as variola virus. This review focuses on the efforts to identify CD8(+) T-Cell epitopes from poxviruses as a means to develop new vaccines and therapeutics. A wide variety of techniques have been employed by several research groups to provide complementary information regarding cellular immune responses to poxviruses. In the last several years well over 100 T-Cell epitopes have been identified and the work rapidly continues. The information gleaned from these studies will not only give us a greater understanding of immunity to variola virus and other viruses, but also provide a foundation for next generation vaccines and additional tools with which to study host-pathogen interactions.

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Human population-based identification of CD4+ T-cell peptide epitope determinants

Cited by 15 publications

References 45 publications

A β-lactamase with reduced immunogenicity for the targeted delivery of chemotherapeutics using antibody-directed enzyme prodrug therapy

A β-lactamase with reduced immunogenicity for the targeted delivery of chemotherapeutics using antibody-directed enzyme prodrug therapy

Development of a Human Antibody Tolerant Mouse Model to Assess the Immunogenicity Risk Due to Aggregated Biotherapeutics

T‐Cell epitope discovery for variola and vaccinia viruses

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