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Article ; Online: Efanesoctocog alfa: the renaissance of Factor VIII replacement therapy.

Dargaud, Yesim / Leuci, Alexandre / Ruiz, Alejandra Reyes / Lacroix-Desmazes, Sebastien

2024

Abstract: Efanesoctocog alfa (ALTUVIIIOTM, Sanofi-SOBI) is a B domain-deleted single-chain Factor VIII (FVIII) connected to D'D3 domain of von Willebrand Factor (VWF). Its ingenious design allows efanesoctocog alfa to operate independently of endogenous VWF and ... ...

Abstract	Efanesoctocog alfa (ALTUVIIIOTM, Sanofi-SOBI) is a B domain-deleted single-chain Factor VIII (FVIII) connected to D'D3 domain of von Willebrand Factor (VWF). Its ingenious design allows efanesoctocog alfa to operate independently of endogenous VWF and results in an outstanding 3-4 times longer half-life compared to standard and extended half-life (EHL) FVIII products. The prolonged half-life ensures sustained high levels of factor activity, maintaining normal to near-normal ranges for the majority of the week, facilitating the convenience of once-weekly administration. Efanesoctocog alfa received regulatory approval in 2023 for application in both adults and children with inherited hemophilia A in the United States and Japan. Its sanctioned use encompasses both prophylaxis and on demand treatment for bleeding episodes. The European Medicines Agency (EMA) is currently undertaking a comprehensive review of ALTUVIIIOTM. This comprehensive review focuses on the immunological profile of efanesoctocog alfa, a highly sophisticated new class of EHL FVIII molecule. The integration of the VWF D'D3 domain, XTEN polypeptides, and potential regulatory T-cell epitopes within various segments of efanesoctocog alfa collectively serves as a mitigating factor against the development of a neutralizing T-cell-mediated immune response. We hypothesize that such distinctive attribute may significantly reduce the risk of neutralizing antibodies, particularly in previously untreated patients. The discussion extends beyond regulatory approval to encompass the preclinical and clinical development of efanesoctocog alfa, including considerations for laboratory monitoring. The review also highlights areas that warrant further investigation to deepen our understanding of this groundbreaking therapeutic agent.
Language	English
Publishing date	2024-02-15
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2023.284498
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Article ; Online: The use of Bacillus subtilis as a cost-effective expression system for production of Cholera Toxin B fused factor VIII epitope regions applicable for inducing oral immune tolerance.

Vijayakumar, Vijay Elakkya / Vijayalakshmi, Mookambeswaran A / Lacroix-Desmazes, Sebastien / Venkataraman, Krishnan

Folia microbiologica

2024

Abstract: Coagulation factor replacement therapy for the X-linked bleeding disorder Haemophilia, characterized by a deficiency of coagulation protein factor VIII (FVIII), is severely complicated by antibody (inhibitors) formation. The development of FVIII ... ...

Abstract	Coagulation factor replacement therapy for the X-linked bleeding disorder Haemophilia, characterized by a deficiency of coagulation protein factor VIII (FVIII), is severely complicated by antibody (inhibitors) formation. The development of FVIII inhibitors drastically alters the quality of life of the patients and is associated with a tremendous increase in morbidity as well as treatment costs. The ultimate goal of inhibitor control is antibody elimination. Immune tolerance induction (ITI) is the only clinically established approach for developing antigen-specific tolerance to FVIII. This work aims to establish a novel cost-effective strategy to produce FVIII molecules in fusion with cholera toxin B (CTB) subunit at the N terminus using the Bacillus subtilis expression system for oral tolerance, as the current clinical immune tolerance protocols are expensive. Regions of B-Domain Deleted (BDD)-FVIII that have potential epitopes were identified by employing Bepipred linear epitope prediction; 2 or more epitopes in each domain were combined and cDNA encoding these regions were fused with CTB and cloned in the Bacillus subtilis expression vector pHT43 and expression analysis was carried out. The expressed CTB-fused FVIII epitope domains showed strong binding affinity towards the CTB-receptor GM1 ganglioside. To conclude, Bacillus subtilis expressing FVIII molecules might be a promising candidate for exploring for the induction of oral immune tolerance.
Language	English
Publishing date	2024-04-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	240503-9
ISSN	1874-9356 ; 0015-5632
ISSN (online)	1874-9356
ISSN	0015-5632
DOI	10.1007/s12223-024-01166-z
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Zs.A 845: Show issues

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Article ; Online: A molecular jewel for hemophilia A treatment.

Rayes, Julie / Lacroix-Desmazes, Sébastien

Blood

2020 Volume 135, Issue 17, Page(s) 1417–1419

MeSH term(s)	Animals ; Factor VIII/genetics ; Hemophilia A/genetics ; Hemophilia A/therapy ; Mice ; Primates ; Recombinant Fusion Proteins ; von Willebrand Factor
Chemical Substances	BIVV001 ; Recombinant Fusion Proteins ; von Willebrand Factor ; Factor VIII (9001-27-8)
Language	English
Publishing date	2020-04-23
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2020005250
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Uh III Zs.140: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 364: Show issues

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Article ; Online: Editorial: Tolerating Factor VIII: Novel Strategies to Prevent and Reverse Neutralizing Anti-FVIII Antibodies.

Lacroix-Desmazes, Sébastien / Pratt, Kathleen P

Frontiers in immunology

2021 Volume 11, Page(s) 639386

MeSH term(s)	Antibodies, Neutralizing/immunology ; Blood Coagulation Factor Inhibitors/immunology ; Factor VIII/adverse effects ; Factor VIII/immunology ; Factor VIII/therapeutic use ; Hemophilia A/drug therapy ; Hemophilia A/immunology ; Humans ; Immune Tolerance
Chemical Substances	Antibodies, Neutralizing ; Blood Coagulation Factor Inhibitors ; F8 protein, human (839MOZ74GK) ; Factor VIII (9001-27-8)
Language	English
Publishing date	2021-01-25
Publishing country	Switzerland
Document type	Editorial ; Introductory Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.639386
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Article ; Online: Pathogenic immune response to therapeutic factor VIII: exacerbated response or failed induction of tolerance?

Varthaman, Aditi / Lacroix-Desmazes, Sébastien

Haematologica

2018 Volume 104, Issue 2, Page(s) 236–244

Abstract: Therapeutic factor VIII is highly immunogenic. Despite intensive research in the last decades, the reasons why 5-30% of patients with hemophilia A (of all severities) develop inhibitory anti-factor VIII antibodies (inhibitors) following replacement ... ...

Abstract	Therapeutic factor VIII is highly immunogenic. Despite intensive research in the last decades, the reasons why 5-30% of patients with hemophilia A (of all severities) develop inhibitory anti-factor VIII antibodies (inhibitors) following replacement therapy remain an enigma. Under physiological conditions, endogenous factor VIII is recognized by the immune system. Likewise, numerous observations indicate that, in hemophilia A patients without inhibitors, exogenous therapeutic factor VIII is immunologically assessed and tolerated. A large part of the research on the immunogenicity of therapeutic factor VIII is attempting to identify the 'danger signals' that act as adjuvants to the deleterious anti-factor VIII immune responses. However, several of the inflammatory assaults concomitant to factor VIII administration initially hypothesized as potential sources of danger signals (e.g., bleeding, infection, and vaccination) have been disproved to be such signals. Conversely, recent evidence suggests that cells from inhibitor-negative patients are able to activate anti-inflammatory and tolerogenic mechanisms required to suppress deleterious immune responses, while cells from inhibitor-positive patients are not. Based on the available observations, we propose a model in which all hemophilia A patients develop anti-factor VIII immune responses during replacement therapy irrespective of associated danger signals. We further postulate that the onset of clinically relevant factor VIII inhibitors results from an inability to develop counteractive tolerogenic responses to exogenous factor VIII rather than from an exacerbated activation of the immune system at the time of factor VIII administration. A better understanding of the pathogenesis of neutralizing anti-factor VIII antibodies will have repercussions on the clinical management of patients and highlight new strategies to achieve active immune tolerance to therapeutic factor VIII.
MeSH term(s)	Blood Coagulation Factor Inhibitors/immunology ; Factor VIII/administration & dosage ; Factor VIII/immunology ; Factor VIII/therapeutic use ; Hemophilia A/blood ; Hemophilia A/complications ; Hemophilia A/drug therapy ; Hemophilia A/immunology ; Hemorrhage/etiology ; Humans ; Immune System/immunology ; Immune System/metabolism ; Immune Tolerance ; Inflammation/complications ; Inflammation/metabolism ; Isoantibodies/immunology ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; Treatment Failure
Chemical Substances	Blood Coagulation Factor Inhibitors ; Isoantibodies ; F8 protein, human (839MOZ74GK) ; Factor VIII (9001-27-8)
Language	English
Publishing date	2018-12-04
Publishing country	Italy
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2018.206383
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Article ; Online: Inhibitors-Recent insights.

Pratt, Kathleen P / Arruda, Valder R / Lacroix-Desmazes, Sébastien

Haemophilia : the official journal of the World Federation of Hemophilia

2020 Volume 27 Suppl 3, Page(s) 28–36

Abstract: The development of inhibitory antibodies to therapeutic factor VIII (FVIII) in haemophilia A (HA) patients is the major complication in treatment/prevention of haemorrhages. The reasons some HA patients develop inhibitors while others do not remain ... ...

Abstract	The development of inhibitory antibodies to therapeutic factor VIII (FVIII) in haemophilia A (HA) patients is the major complication in treatment/prevention of haemorrhages. The reasons some HA patients develop inhibitors while others do not remain unclear. This review briefly summarizes our understanding of anti-FVIII immune responses, the roles of T cells, both effector and regulatory, and generally discusses the interplay between FVIII and the immune system, both in factor replacement therapy and gene therapy, with some comparisons to factor IX and haemophilia B therapies. Notably, we propose that the prevailing observed active tolerance to FVIII in both HA and non-HA individuals rests to greater or lesser extents on peripherally induced immune tolerance. We also propose that the immune systems of inhibitor-negative HA patients do not merely ignore therapeutic FVIII, but rather have immunologically assessed and actively tolerized the patients to exogenous FVIII. Induction of such peripheral immune tolerance may further be triggered in HA patients who failed to tolerize upon initial FVIII exposure by 'appropriate' stimulation of their immune system, eg by immune tolerance induction therapy via intensive FVIII therapy, by oral administration of FVIII, by cellular therapies or by gene therapy directed to immuno-tolerogenic sites such as the liver.
MeSH term(s)	Factor VIII/genetics ; Genetic Therapy ; Hemophilia A/drug therapy ; Hemostatics ; Humans ; Immune Tolerance
Chemical Substances	Hemostatics ; Factor VIII (9001-27-8)
Language	English
Publishing date	2020-06-30
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1229713-6
ISSN	1365-2516 ; 1351-8216 ; 1355-0691
ISSN (online)	1365-2516
ISSN	1351-8216 ; 1355-0691
DOI	10.1111/hae.14077
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Zs.A 4249: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 450: Show issues

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Article ; Online: Noncanonical Functions of Antibodies.

Dimitrov, Jordan D / Lacroix-Desmazes, Sébastien

Trends in immunology

2020 Volume 41, Issue 5, Page(s) 379–393

Abstract: The typical functions of antibodies are based on linking the process of antigen recognition with initiation of innate immune reactions. With the introduction of modern research technologies and the use of sophisticated model systems, recent years have ... ...

Abstract	The typical functions of antibodies are based on linking the process of antigen recognition with initiation of innate immune reactions. With the introduction of modern research technologies and the use of sophisticated model systems, recent years have witnessed the discovery of a number of noncanonical functions of antibodies. These functions encompass either untypical strategies for neutralization of pathogens or exertion of activities that are characteristic for other proteins (cytokines, chaperones, or enzymes). Here, we provide an overview of the noncanonical functions of antibodies and discuss their mechanisms and implications in immune regulation and defense. A better comprehension of these functions will enrich our knowledge of the adaptive immune response and shall inspire the development of novel therapeutics.
MeSH term(s)	Adaptive Immunity ; Antibodies/immunology ; Humans ; Immune System/immunology
Chemical Substances	Antibodies
Keywords	covid19
Language	English
Publishing date	2020-04-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2036831-8
ISSN	1471-4981 ; 1471-4906
ISSN (online)	1471-4981
ISSN	1471-4906
DOI	10.1016/j.it.2020.03.006
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Zs.A 1601: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 2: Show issues

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Article ; Online: Emerging benefits of Fc fusion technology in the context of recombinant factor VIII replacement therapy.

Meeks, Shannon L / Lacroix-Desmazes, Sébastien

Haemophilia : the official journal of the World Federation of Hemophilia

2020 Volume 26, Issue 6, Page(s) 958–965

Abstract: Although the primary reason for recombinant factor VIII Fc fusion protein (rFVIIIFc) development was to reduce treatment burden associated with routine prophylaxis, new evidence suggests additional benefits of Fc fusion technology in the treatment of ... ...

Abstract	Although the primary reason for recombinant factor VIII Fc fusion protein (rFVIIIFc) development was to reduce treatment burden associated with routine prophylaxis, new evidence suggests additional benefits of Fc fusion technology in the treatment of people with haemophilia A. Preclinical research has been utilized to characterize the potential immunomodulatory properties of rFVIIIFc, including an ability to reduce inflammation and induce tolerance to factor VIII. This has since been expanded into clinical research in immune tolerance induction (ITI) with rFVIIIFc, results of which suggest the potential for rapid tolerization in first-time ITI patients and therapeutic benefit in patients undergoing rescue ITI. The potential for improved joint health through the anti-inflammatory properties of rFVIIIFc has also been suggested. In addition, a new avenue of research into the role of rFVIIIFc in promoting bone health in patients with haemophilia A, potentially through reduced osteoclast formation, has yielded encouraging results that support further study. This review summarizes the existing preclinical and clinical studies of immunomodulation and tolerization with rFVIIIFc, as well as studies in joint and bone health, to elucidate the potential benefits of rFVIIIFc in haemophilia A beyond the extension of factor VIII half-life.
MeSH term(s)	Factor VIII/pharmacology ; Factor VIII/therapeutic use ; Female ; Hemophilia A/drug therapy ; Humans ; Immunoglobulin Fc Fragments/pharmacology ; Immunoglobulin Fc Fragments/therapeutic use ; Male ; Recombinant Fusion Proteins/pharmacology ; Recombinant Fusion Proteins/therapeutic use
Chemical Substances	Immunoglobulin Fc Fragments ; Recombinant Fusion Proteins ; factor VIII-Fc fusion protein ; Factor VIII (9001-27-8)
Language	English
Publishing date	2020-09-03
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1229713-6
ISSN	1365-2516 ; 1351-8216 ; 1355-0691
ISSN (online)	1365-2516
ISSN	1351-8216 ; 1355-0691
DOI	10.1111/hae.14123
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Zs.A 4249: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 450: Show issues

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Article ; Online: Vaccine-induced immune thrombotic thrombocytopenia: Consider IVIG batch in the treatment.

Karnam, Anupama / Lacroix-Desmazes, Sébastien / Kaveri, Srini V / Bayry, Jagadeesh

Journal of thrombosis and haemostasis : JTH

2021 Volume 19, Issue 7, Page(s) 1838–1839

MeSH term(s)	Humans ; Immunoglobulins, Intravenous/adverse effects ; Purpura, Thrombocytopenic, Idiopathic/chemically induced ; Purpura, Thrombocytopenic, Idiopathic/diagnosis ; Purpura, Thrombocytopenic, Idiopathic/drug therapy ; Thrombocytopenia ; Thrombosis ; Vaccines
Chemical Substances	Immunoglobulins, Intravenous ; Vaccines
Language	English
Publishing date	2021-04-30
Publishing country	England
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1111/jth.15361
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Zs.A 5805: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Oxidized hemoglobin triggers polyreactivity and autoreactivity of human IgG via transfer of heme.

Planchais, Cyril / Noe, Remi / Gilbert, Marie / Lecerf, Maxime / Kaveri, Srini V / Lacroix-Desmazes, Sébastien / Roumenina, Lubka T / Dimitrov, Jordan D

Communications biology

2023 Volume 6, Issue 1, Page(s) 168

Abstract: Intravascular hemolysis occurs in diverse pathological conditions. Extracellular hemoglobin and heme have strong pro-oxidative and pro-inflammatory potentials that can contribute to the pathology of hemolytic diseases. However, many of the effects of ... ...

Abstract	Intravascular hemolysis occurs in diverse pathological conditions. Extracellular hemoglobin and heme have strong pro-oxidative and pro-inflammatory potentials that can contribute to the pathology of hemolytic diseases. However, many of the effects of extracellular hemoglobin and heme in hemolytic diseases are still not well understood. Here we demonstrate that oxidized hemoglobin (methemoglobin) can modify the antigen-binding characteristics of human immunoglobulins. Thus, incubation of polyclonal or some monoclonal human IgG in the presence of methemoglobin results in an appearance of binding reactivities towards distinct unrelated self-proteins, including the protein constituent of hemoglobin i.e., globin. We demonstrate that a transfer of heme from methemoglobin to IgG is indispensable for this acquisition of antibody polyreactivity. Our data also show that only oxidized form of hemoglobin have the capacity to induce polyreactivity of antibodies. Site-directed mutagenesis of a heme-sensitive human monoclonal IgG1 reveals details about the mechanism of methemoglobin-induced antigen-binding polyreactivity. Further here we assess the kinetics and thermodynamics of interaction of a heme-induced polyreactive human antibody with hemoglobin and myoglobin. Taken together presented data contribute to a better understanding of the functions of extracellular hemoglobin in the context of hemolytic diseases.
MeSH term(s)	Humans ; Heme/metabolism ; Methemoglobin/metabolism ; Hemoglobins/metabolism ; Immunoglobulin G ; Antibodies, Monoclonal ; Hemolysis
Chemical Substances	Heme (42VZT0U6YR) ; Methemoglobin (9008-37-1) ; Hemoglobins ; Immunoglobulin G ; Antibodies, Monoclonal
Language	English
Publishing date	2023-02-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-023-04535-5
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