Combinatorial peptides directed to inhibitory antibodies against human blood clotting factor VIII

Kopecky, Eva-Maria; Greinstetter, Sabine; Pabinger, Ingrid; Buchacher, Andrea; Römisch, Jürgen; Jungbauer, Alois

doi:10.1160/th05-04-0254

Cited by 15 publications

(16 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Alternative protein and nonprotein agents are showing promise in preclinical development. Kopecky et al 48 synthetically designed peptide sequences that were screened and tested for their ability to bind to inhibitory antibodies effectively neutralizing anti-FVIII antibodies in vitro. The promising peptides typically have sequences that are similar to FVIII.…”

Section: Alternative Hemostatic Agentsmentioning

confidence: 99%

Hemophilia: New Protein Therapeutics

Pipe

2010

Hematology

View full text Add to dashboard Cite

Therapeutic advances for patients with hemophilia have resulted in reduced mortality, improved joint outcomes, safety from blood-transmitted pathogens, improved quality of life, and a normalized life span in the developed world. The production of recombinant coagulation factors has increased the worldwide capacity for replacement therapy and facilitated aggressive prophylactic therapy. However, this has come at significant cost, and barriers remain to broad application of prophylaxis. Recombinant DNA technology remains a promising platform to develop novel hemophilia therapeutics with improved functional properties to try to overcome some of these remaining barriers. Bioengineering strategies have produced novel therapeutics with increased production efficiency, increased potency and resistance to inactivation, prolonged plasma half-lives, and reduced immunogenicity. Alternative nonbiologic therapies may lead to new treatment paradigms. The current pipeline of new technologies and products is promising and growing with several agents already advancing from preclinical to clinical trials.

show abstract

Section: Alternative Hemostatic Agentsmentioning

confidence: 99%

Hemophilia: New Protein Therapeutics

Pipe

2010

Hematology

View full text Add to dashboard Cite

show abstract

“…Recentemente, um grupo de pesquisadores atestou, pela técnica de Spot, que a cadeia leve do FVIII é reconhecida por uma variedade maior de anticorpos e sugere que o domínio C1 é o mais imunogênico. 66,67 A maioria dos inibidores que reconhecem a cadeia leve da molécula de FVIII se liga ao domínio C2, [68][69][70][71] que possui dois sítios de reconhecimento bem caracterizados. Estes anticorpos impedem a ligação do FVIII ativado ao FvW e aos fosfolipídios de membrana, impedindo a formação do complexo tenaz.…”

Section: Perspectivas De Tratamentounclassified

Desenvolvimento de inibidores do fator VIII na hemofilia A

Chaves¹,

Rodrigues²

2009

Rev. Bras. Hematol. Hemoter.

View full text Add to dashboard Cite

Dentre os distúrbios de coagulação hereditários nas populações humanas destaca-se, por sua gravidade, a hemofilia A (HA), uma coagulopatia recessiva ligada ao cromossomo X causada pela deficiência ou disfunção da glicoproteína plasmática denominada Fator VIII (FVIII). A incidência da HA pode chegar a 1:5.000 meninos nascidos vivos. Nos indivíduos com hemofilia A grave (aproximadamente 50% dos casos; atividade do FVIII<0,01 U/mL), a hemorragia pode ocorrer espontaneamente, enquanto Dias, pacientes com hemofilia moderada (cerca de 10% dos indiví-duos; atividade do FVIII 0.01-0.05 U/mL) apresentam um fenótipo intermediário. Pacientes portadores da forma leve da doença, observada em 30%-40% dos casos (atividade do FVIII 0,05-0,4 U/mL), sofrem de hemorragias pós-trauma ou pós-cirúrgicas. REVISTA BRASILEIRA DE HEMATOLOGIA E H E M O T E R A P I A 1As anormalidades genéticas responsáveis pela hemofilia congênita incluem deleções, inversões (mais frequentemente a inversão do intron 22), mutações sem sentido, mutações de sentido trocado e pequenas deleções no

show abstract

“…They reported findings of peptides containing FVIII-mimotopes that were able to restore FVIII activity. Kopecky et al (2005) presented decapeptides from a combinatorial peptide library directed against FVIII inhibitors from patient's sera. However, a restoration of FVIII activity in presence of inhibitors could not be demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Peptides derived from a secretory yeast library restore factor VIII activity in the presence of an inhibitory antibody

Mersich

Billes

Pabinger

et al. 2007

Biotech & Bioengineering

Self Cite

View full text Add to dashboard Cite

The development of autoantibodies against factor VIII represents one of the major complications in the treatment of hemophilia A patients. We have employed a novel library system to obtain peptides that specifically neutralize the interaction between factor VIII and these inhibitors. The random peptides are presented as carboxy-terminal extensions of the eukaryotic initiation factor 5a, an intracellular protein with a molecular mass of 18 kDa. These random peptides formed an unique binding site, as demonstrated by molecular simulations using the computer programs InsightII and GROMACS. The library was screened to identify peptides binding to the murine monoclonal anti-factor VIII antibody ESH8 and to inhibitors derived from patients with factor VIII antibodies. Ten peptides binding to ESH8 were identified. Their specificity was confirmed by displacement assays. Two peptides with the sequences STKTLGRPLHGPAGPVEGGALAGVAEDADLVTAVSGR and YHCKREDLTDRDATCALRQPPQAVRGLGPRVTAVSGR showed the ability to restore the factor VIII activity from 33% up to approximately 90% in functional tests performed in vitro. Three candidates for binding to factor VIII antibodies derived from four different patient's sera were achieved. Three fusion proteins with the peptide sequences PQLGSRRSTTPSLTFQNASWFPAGGPCARSNRG, SGSRQVCKLARSLQPF and WERGRRVGAQVRHARHLVARVLDGAGHQARLTAVNGP bound to inhibitors derived from different patients. Furthermore, two of the obtained fusion proteins with the peptide sequences RHWTALGPAPTHTCADLNYPLLS and WERGRRVGAQVRHARHLVARVLDGAGHQARLTAVNGP did also bind to the monoclonal antibody ESH8. This study demonstrates the potential of this system to identify peptides that inhibit the activity of potent inhibitory antibodies and also shows potential as a method for screening of bioactive peptides.

show abstract

Combinatorial peptides directed to inhibitory antibodies against human blood clotting factor VIII

Cited by 15 publications

References 37 publications

Hemophilia: New Protein Therapeutics

Hemophilia: New Protein Therapeutics

Desenvolvimento de inibidores do fator VIII na hemofilia A

Peptides derived from a secretory yeast library restore factor VIII activity in the presence of an inhibitory antibody

Contact Info

Product

Resources

About