Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity

J. N. Mahlangu, K. N. Weldingh, S. R. Lentz, S. Kaicker, F. A. Karim, T. Matsushita, M. Recht, W. Tomczak, J. Windyga, S. Ehrenforth, K. Knobe, Ansgar Weltermann, E. de Paula, Monica Cerqueira, Silva Zupancic-Salek, Olga Katsarou, Marina Economou, Laszlo Nemes, Zoltan Boda, Elena Santagostino & 22 others Giuseppe Tagariello, Hideji Hanabusa, Katsuyuki Fukutake, Midori Shima, Margit Serban, I. Elezo-vic, Aleksandar Savic, Ming Shen, Ampaiwan Chuansumrit, Pantep Angchaisuksiri, Kaan Kavakli, Ilgen Sasmaz, Bella Madan, Paul Giangrande, Christine Kempton, Guy Young, Doris Quon, Afshin Ameri, Philip Kuriakose, Dana Obzut, Michael Wang, Idith Ortiz

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background: Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophilia patients with inhibitors, differs from native FVIIa by three amino acid substitutions. In a randomized, double-blind, crossover, confirmatory phase III trial (adept 2), 8/72 (11%) hemophilia A or B patients with inhibitors treated for acute bleeds developed anti-drug antibodies (ADAs) to vatreptacog alfa. Objectives: To characterize the formation of anti-vatreptacog alfa ADAs in hemophilia patients with inhibitors. Methods/patients: This was a post hoc analysis of adept 2. Immunoglobulin isotype determination, specificity analysis of rFVIIa cross-reactive antibodies, epitope mapping of rFVIIa single mutant analogs and pharmacokinetic (PK) profiling were performed to characterize the ADAs. Results: Immunoglobulin isotyping indicated that the ADAs were of the immunoglobulin G subtype. In epitope mapping, none of the rFVIIa single mutant analogs (V158D, E296V or M298Q) contained the complete antibody epitope, confirming that the antibodies were specific for vatreptacog alfa. In two patients, for whom PK profiling was performed both before and after the development of ADAs, vatreptacog alfa showed a prolonged elimination phase following ADA development. During the follow-up evaluation, the rFVIIa cross-reactivity disappeared after the last vatreptacog alfa exposure, despite continued exposure to rFVIIa as part of standard care. Conclusions: Results from the vatreptacog alfa phase III trial demonstrate that the specific changes made, albeit relatively small, to the FVIIa molecule alter its clinical immunogenicity.

Original languageEnglish (US)
Pages (from-to)1989-1998
Number of pages10
JournalJournal of Thrombosis and Haemostasis
Volume13
Issue number11
DOIs
StatePublished - Nov 1 2015

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Amino Acid Sequence
Anti-Idiotypic Antibodies
Hemophilia A
Pharmaceutical Preparations
Epitope Mapping
Antibodies
Pharmacokinetics
Hemophilia B
Immunoglobulin Isotypes
Amino Acid Substitution
Standard of Care
vatreptacog alfa
recombinant FVIIa
Immunoglobulins
Epitopes
Immunoglobulin G

Keywords

  • Antibodies
  • Antibody formation
  • Hemophilia
  • Immunoglobulin isotypes
  • Recombinant factor VIIa
  • Vatreptacog alfa

ASJC Scopus subject areas

  • Hematology

Cite this

Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity. / Mahlangu, J. N.; Weldingh, K. N.; Lentz, S. R.; Kaicker, S.; Karim, F. A.; Matsushita, T.; Recht, M.; Tomczak, W.; Windyga, J.; Ehrenforth, S.; Knobe, K.; Weltermann, Ansgar; de Paula, E.; Cerqueira, Monica; Zupancic-Salek, Silva; Katsarou, Olga; Economou, Marina; Nemes, Laszlo; Boda, Zoltan; Santagostino, Elena; Tagariello, Giuseppe; Hanabusa, Hideji; Fukutake, Katsuyuki; Shima, Midori; Serban, Margit; Elezo-vic, I.; Savic, Aleksandar; Shen, Ming; Chuansumrit, Ampaiwan; Angchaisuksiri, Pantep; Kavakli, Kaan; Sasmaz, Ilgen; Madan, Bella; Giangrande, Paul; Kempton, Christine; Young, Guy; Quon, Doris; Ameri, Afshin; Kuriakose, Philip; Obzut, Dana; Wang, Michael; Ortiz, Idith.

In: Journal of Thrombosis and Haemostasis, Vol. 13, No. 11, 01.11.2015, p. 1989-1998.

Research output: Contribution to journalArticle

Mahlangu, JN, Weldingh, KN, Lentz, SR, Kaicker, S, Karim, FA, Matsushita, T, Recht, M, Tomczak, W, Windyga, J, Ehrenforth, S, Knobe, K, Weltermann, A, de Paula, E, Cerqueira, M, Zupancic-Salek, S, Katsarou, O, Economou, M, Nemes, L, Boda, Z, Santagostino, E, Tagariello, G, Hanabusa, H, Fukutake, K, Shima, M, Serban, M, Elezo-vic, I, Savic, A, Shen, M, Chuansumrit, A, Angchaisuksiri, P, Kavakli, K, Sasmaz, I, Madan, B, Giangrande, P, Kempton, C, Young, G, Quon, D, Ameri, A, Kuriakose, P, Obzut, D, Wang, M & Ortiz, I 2015, 'Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity', Journal of Thrombosis and Haemostasis, vol. 13, no. 11, pp. 1989-1998. https://doi.org/10.1111/jth.13141
Mahlangu, J. N. ; Weldingh, K. N. ; Lentz, S. R. ; Kaicker, S. ; Karim, F. A. ; Matsushita, T. ; Recht, M. ; Tomczak, W. ; Windyga, J. ; Ehrenforth, S. ; Knobe, K. ; Weltermann, Ansgar ; de Paula, E. ; Cerqueira, Monica ; Zupancic-Salek, Silva ; Katsarou, Olga ; Economou, Marina ; Nemes, Laszlo ; Boda, Zoltan ; Santagostino, Elena ; Tagariello, Giuseppe ; Hanabusa, Hideji ; Fukutake, Katsuyuki ; Shima, Midori ; Serban, Margit ; Elezo-vic, I. ; Savic, Aleksandar ; Shen, Ming ; Chuansumrit, Ampaiwan ; Angchaisuksiri, Pantep ; Kavakli, Kaan ; Sasmaz, Ilgen ; Madan, Bella ; Giangrande, Paul ; Kempton, Christine ; Young, Guy ; Quon, Doris ; Ameri, Afshin ; Kuriakose, Philip ; Obzut, Dana ; Wang, Michael ; Ortiz, Idith. / Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity. In: Journal of Thrombosis and Haemostasis. 2015 ; Vol. 13, No. 11. pp. 1989-1998.
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abstract = "Background: Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophilia patients with inhibitors, differs from native FVIIa by three amino acid substitutions. In a randomized, double-blind, crossover, confirmatory phase III trial (adept ™ 2), 8/72 (11{\%}) hemophilia A or B patients with inhibitors treated for acute bleeds developed anti-drug antibodies (ADAs) to vatreptacog alfa. Objectives: To characterize the formation of anti-vatreptacog alfa ADAs in hemophilia patients with inhibitors. Methods/patients: This was a post hoc analysis of adept ™ 2. Immunoglobulin isotype determination, specificity analysis of rFVIIa cross-reactive antibodies, epitope mapping of rFVIIa single mutant analogs and pharmacokinetic (PK) profiling were performed to characterize the ADAs. Results: Immunoglobulin isotyping indicated that the ADAs were of the immunoglobulin G subtype. In epitope mapping, none of the rFVIIa single mutant analogs (V158D, E296V or M298Q) contained the complete antibody epitope, confirming that the antibodies were specific for vatreptacog alfa. In two patients, for whom PK profiling was performed both before and after the development of ADAs, vatreptacog alfa showed a prolonged elimination phase following ADA development. During the follow-up evaluation, the rFVIIa cross-reactivity disappeared after the last vatreptacog alfa exposure, despite continued exposure to rFVIIa as part of standard care. Conclusions: Results from the vatreptacog alfa phase III trial demonstrate that the specific changes made, albeit relatively small, to the FVIIa molecule alter its clinical immunogenicity.",
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TY - JOUR

T1 - Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity

AU - Mahlangu, J. N.

AU - Weldingh, K. N.

AU - Lentz, S. R.

AU - Kaicker, S.

AU - Karim, F. A.

AU - Matsushita, T.

AU - Recht, M.

AU - Tomczak, W.

AU - Windyga, J.

AU - Ehrenforth, S.

AU - Knobe, K.

AU - Weltermann, Ansgar

AU - de Paula, E.

AU - Cerqueira, Monica

AU - Zupancic-Salek, Silva

AU - Katsarou, Olga

AU - Economou, Marina

AU - Nemes, Laszlo

AU - Boda, Zoltan

AU - Santagostino, Elena

AU - Tagariello, Giuseppe

AU - Hanabusa, Hideji

AU - Fukutake, Katsuyuki

AU - Shima, Midori

AU - Serban, Margit

AU - Elezo-vic, I.

AU - Savic, Aleksandar

AU - Shen, Ming

AU - Chuansumrit, Ampaiwan

AU - Angchaisuksiri, Pantep

AU - Kavakli, Kaan

AU - Sasmaz, Ilgen

AU - Madan, Bella

AU - Giangrande, Paul

AU - Kempton, Christine

AU - Young, Guy

AU - Quon, Doris

AU - Ameri, Afshin

AU - Kuriakose, Philip

AU - Obzut, Dana

AU - Wang, Michael

AU - Ortiz, Idith

PY - 2015/11/1

Y1 - 2015/11/1

N2 - Background: Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophilia patients with inhibitors, differs from native FVIIa by three amino acid substitutions. In a randomized, double-blind, crossover, confirmatory phase III trial (adept ™ 2), 8/72 (11%) hemophilia A or B patients with inhibitors treated for acute bleeds developed anti-drug antibodies (ADAs) to vatreptacog alfa. Objectives: To characterize the formation of anti-vatreptacog alfa ADAs in hemophilia patients with inhibitors. Methods/patients: This was a post hoc analysis of adept ™ 2. Immunoglobulin isotype determination, specificity analysis of rFVIIa cross-reactive antibodies, epitope mapping of rFVIIa single mutant analogs and pharmacokinetic (PK) profiling were performed to characterize the ADAs. Results: Immunoglobulin isotyping indicated that the ADAs were of the immunoglobulin G subtype. In epitope mapping, none of the rFVIIa single mutant analogs (V158D, E296V or M298Q) contained the complete antibody epitope, confirming that the antibodies were specific for vatreptacog alfa. In two patients, for whom PK profiling was performed both before and after the development of ADAs, vatreptacog alfa showed a prolonged elimination phase following ADA development. During the follow-up evaluation, the rFVIIa cross-reactivity disappeared after the last vatreptacog alfa exposure, despite continued exposure to rFVIIa as part of standard care. Conclusions: Results from the vatreptacog alfa phase III trial demonstrate that the specific changes made, albeit relatively small, to the FVIIa molecule alter its clinical immunogenicity.

AB - Background: Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophilia patients with inhibitors, differs from native FVIIa by three amino acid substitutions. In a randomized, double-blind, crossover, confirmatory phase III trial (adept ™ 2), 8/72 (11%) hemophilia A or B patients with inhibitors treated for acute bleeds developed anti-drug antibodies (ADAs) to vatreptacog alfa. Objectives: To characterize the formation of anti-vatreptacog alfa ADAs in hemophilia patients with inhibitors. Methods/patients: This was a post hoc analysis of adept ™ 2. Immunoglobulin isotype determination, specificity analysis of rFVIIa cross-reactive antibodies, epitope mapping of rFVIIa single mutant analogs and pharmacokinetic (PK) profiling were performed to characterize the ADAs. Results: Immunoglobulin isotyping indicated that the ADAs were of the immunoglobulin G subtype. In epitope mapping, none of the rFVIIa single mutant analogs (V158D, E296V or M298Q) contained the complete antibody epitope, confirming that the antibodies were specific for vatreptacog alfa. In two patients, for whom PK profiling was performed both before and after the development of ADAs, vatreptacog alfa showed a prolonged elimination phase following ADA development. During the follow-up evaluation, the rFVIIa cross-reactivity disappeared after the last vatreptacog alfa exposure, despite continued exposure to rFVIIa as part of standard care. Conclusions: Results from the vatreptacog alfa phase III trial demonstrate that the specific changes made, albeit relatively small, to the FVIIa molecule alter its clinical immunogenicity.

KW - Antibodies

KW - Antibody formation

KW - Hemophilia

KW - Immunoglobulin isotypes

KW - Recombinant factor VIIa

KW - Vatreptacog alfa

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U2 - 10.1111/jth.13141

DO - 10.1111/jth.13141

M3 - Article

VL - 13

SP - 1989

EP - 1998

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

SN - 1538-7933

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ER -