Recombinant Staphylokinase Variants With Altered Immunoreactivity

Collen, D.; Stockx, L; Lacroix, H.; Suy, R; Vanderschueren, Steven

doi:10.1161/01.cir.95.2.463

Cited by 62 publications

(33 citation statements)

References 6 publications

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“…Several SakSTAR variants, with multiple mutations in this area, were tried in patients with peripheral arterial occlusion. Interestingly, the Ab response was found significantly reduced compared with patients treated with wild-type SakSTAR (12,13). The observed reduced humoral response may, however, be explained at least in part by the mutation of an important immunoreactive T cell region in these SakSTAR variants.…”

Section: Discussionmentioning

confidence: 87%

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Staphylokinase-Specific Cell-Mediated Immunity in Humans

Warmerdam

Vanderlick

Vandervoort

et al. 2002

The Journal of Immunology

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Staphylokinase is a highly fibrin-specific clot-dissolving agent that constitutes a promising drug for clinical development. It is of bacterial origin, and the majority of patients develop neutralizing Ab after its administration. Several antigenic regions, recognized by these Ab, have been identified, but the underlying immunogenic features of staphylokinase remain unknown. In this study, we show that staphylokinase is a T cell-dependent Ag, and that an immunological memory may be acquired, even without administration of staphylokinase. Thrombolysis with staphylokinase provokes the proliferation of staphylokinase-specific T lymphocytes, which remain elevated over 10 mo posttreatment. Interestingly, analysis of a large number of staphylokinase-specific T cell clones isolated from 10 unrelated donors revealed only six distinct immunogenic regions in the molecule. Moreover, five of the six regions are recognized by T lymphocytes from several individuals, indicating that these regions are not restricted to a single HLA-DR allele. Therefore, these new insights can guide the design of variants with a lower immunogenic profile in humans.

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Section: Discussionmentioning

confidence: 87%

“…Mutagenesis studies within these regions indicated that modification of several surface-exposed amino acids of the SakSTAR molecule is possible without substantial loss of its thrombolytic potency. Significantly less neutralizing Ab were found after administration of some variants as compared with patients treated with wild-type SakSTAR (12,13).…”

mentioning

confidence: 91%

Staphylokinase-Specific Cell-Mediated Immunity in Humans

Warmerdam

Vanderlick

Vandervoort

et al. 2002

The Journal of Immunology

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“…The strategy of mutating B-cell epitopes to reduce immunogenicity has also been applied with success by other workers for staphylokinase (Collen et al, 1996) and L-asparaginase (Moola et al, 1994). This is however, to our knowledge, the first reported instance of successful masking of an immunogenic epitope by addition of a His-tag.…”

Section: Discussionmentioning

confidence: 94%

Modifying an immunogenic epitope on a therapeutic protein: a step towards an improved system for antibody-directed enzyme prodrug therapy (ADEPT)

et al. 2004

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Carboxypeptidase G2 (CP) is a bacterial enzyme, which is targeted to tumours by an antitumour antibody for local prodrug activation in antibody-directed enzyme prodrug therapy (ADEPT). Repeated cycles of ADEPT are desirable but are hampered by human antibody response to CP (HACA). To address this, we aimed to identify and modify clinically important immunogenic sites on MFECP, a recombinant fusion protein of CP with MFE-23, a single chain Fv (scFv) antibody. A discontinuous conformational epitope at the C-terminus of the CP previously identified by the CM79 scFv antibody (CM79-identified epitope) was chosen for study. Modification of MFECP was achieved by mutations of the CM79-identified epitope or by addition of a hexahistidine tag (His-tag) to the C-terminus of MFECP, which forms part of the epitope. Murine immunisation experiments with modified MFECP showed no significant antibody response to the CM79-identified epitope compared to A5CP, an unmodified version of CP chemically conjugated to an F(ab) 2 antibody. Success of modification was also demonstrated in humans because patients treated with His-tagged MFECP had a significantly reduced antibody response to the CM79-identified epitope, compared to patients given A5CP. Moreover, the polyclonal antibody response to CP was delayed in both mice and patients given modified MFECP. This increases the prospect of repeated treatment with ADEPT for effective cancer treatment.

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“…The cumulative results of three rounds of expression and screening identified 13 T cell antigens, two of which induce serum antibodies in humans (NWMN_2318 [␥-hemolysin A] and NWMN_2469 [antigen A]) (11)(12)(13) Table 2). The 13 T cell antigens include four putative lipoproteins, three hemolysins, various enzymes, and an alkaline shock protein.…”

Section: Identification Of S Aureus Antigens That Induced Significanmentioning

confidence: 99%

CD4 T Cell Antigens from Staphylococcus aureus Newman Strain Identified following Immunization with Heat-Killed Bacteria

Lawrence¹,

Rokbi²,

Arnaud-Barbe³

et al. 2012

Clin. Vaccine Immunol.

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ABSTRACTStaphylococcus aureusis a commensal bacterium associated with the skin and mucosal surfaces of humans and animals that can also cause chronic infection. The emergence of antibiotic-resistant strains such as methicillin-resistantS. aureus(MRSA) and strains causing chronic intramammary infections (IMI) in cows results in severe human and livestock infections. Conventional approaches to vaccine development have yielded only a few noneffective vaccines against MRSA or IMI strains, so there is a need for improved vaccine development. CD4 T lymphocytes are required for promoting gamma interferon (IFN-γ) mediated immunoglobulin isotype switching in B lymphocytes to produce high-affinity IgG antibodies and IFN-γ-mediated phagocyte activation for an effective resolution of bacterial infection. However, the lack of known CD4 T cell antigens fromS. aureushas made it difficult to design effective vaccines. The goal of this study was to identifyS. aureusproteins recognized by immune CD4 T cells. Using a reverse genetics approach, 43 antigens were selected from theS. aureusNewman strain. These included lipoproteins, proteases, transcription regulators, an alkaline shock protein, conserved-domain proteins, hemolysins, fibrinogen-binding protein, staphylokinase, exotoxin, enterotoxin, sortase, and protein A. Screening of expressed proteins for recall T cell responses in outbred, immune calves identified 13 proteins that share over 80% sequence identity among MRSA or IMI strains. These may be useful for inclusion in a broadly protective multiantigen vaccine against MRSA or IMI.

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Recombinant Staphylokinase Variants With Altered Immunoreactivity

Abstract: SakSTAR(K74), a variant of recombinant staphylokinase with a single substitution of Lys74 with Ala, and SakSTAR(K74), with Lys74, Glu75, and Arg77 substituted with Ala, have intact thrombolytic potencies but induce significantly less antibody formation in patients.

Cited by 62 publications

References 6 publications

Staphylokinase-Specific Cell-Mediated Immunity in Humans

Staphylokinase-Specific Cell-Mediated Immunity in Humans

Modifying an immunogenic epitope on a therapeutic protein: a step towards an improved system for antibody-directed enzyme prodrug therapy (ADEPT)

CD4 T Cell Antigens from Staphylococcus aureus Newman Strain Identified following Immunization with Heat-Killed Bacteria

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