A fully human anti-BMP6 antibody reduces the need for erythropoietin in rodent models of the anemia of chronic disease
Verena Petzer
(1, 2)
,
Piotr Tymoszuk
(1)
,
Malte Asshoff
(1)
,
Joana Carvalho
(3)
,
Jonathan Papworth
(3)
,
Cecilia Deantonio
(3)
,
Luke Bayliss
(3)
,
Matthew Stephen Wake
(3)
,
Markus Seifert
(1, 4)
,
Natascha Brigo
(1)
,
Lara Valente de Souza
(1, 4)
,
Richard Hilbe
(1)
,
Philipp Grubwieser
(1)
,
Egon Demetz
(1)
,
Stefanie Dichtl
(1)
,
Chiara Volani
(1)
,
Sylvia Berger
(1)
,
Felix Böhm
(1)
,
Alexander Hoffmann
(1, 4)
,
Christa Pfeifhofer-Obermair
(1)
,
Laura von Raffay
(1)
,
Sieghart Sopper
,
Stephanie Arndt
(5)
,
Anja Bosserhoff
(6)
,
Léon Kautz
(7)
,
Prunelle Perrier
(7)
,
Manfred Nairz
(1)
,
Dominik Wolf
(2, 8)
,
Guenter Weiss
(1, 4)
,
Volker Germaschewski
(3)
,
Igor Theurl
(1)
1
Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria.
2 Med Univ Innsbruck, Dept Internal Med 5, Hematol & Oncol, Innsbruck, Austria
3 Kymab Ltd, Cambridge, England
4 Med Univ Innsbruck, Christian Doppler Lab Iron Metab & Anemia Res, Innsbruck, Austria
5 Univ Med Ctr Regensburg, Dept Dermatol, Regensburg, Germany
6 Friedrich Alexander Univ Erlangen Nurnberg, Inst Biochem, Emil Fischer Ctr, Erlangen, Germany
7 IRSD - Institut de Recherche en Santé Digestive
8 Univ Clin Bonn, Internal Med 3, Oncol Oncol Immunooncol & Rheumatol, Bonn, Germany
2 Med Univ Innsbruck, Dept Internal Med 5, Hematol & Oncol, Innsbruck, Austria
3 Kymab Ltd, Cambridge, England
4 Med Univ Innsbruck, Christian Doppler Lab Iron Metab & Anemia Res, Innsbruck, Austria
5 Univ Med Ctr Regensburg, Dept Dermatol, Regensburg, Germany
6 Friedrich Alexander Univ Erlangen Nurnberg, Inst Biochem, Emil Fischer Ctr, Erlangen, Germany
7 IRSD - Institut de Recherche en Santé Digestive
8 Univ Clin Bonn, Internal Med 3, Oncol Oncol Immunooncol & Rheumatol, Bonn, Germany
Résumé
Recombinant erythropoietin (EPO) and iron substitution are a standard of care for treatment of anemias associated with chronic inflammation, including anemia of chronic kidney disease. A black box warning for EPO therapy and concerns about negative side effects related to high-dose iron supplementation as well as the significant proportion of patients becoming EPO resistant over time explains the medical need to define novel strategies to ameliorate anemia of chronic disease (ACD). As hepcidin is central to the ironrestrictive phenotype in ACD, therapeutic approaches targeting hepcidin were recently developed. We herein report the therapeutic effects of a fully human anti-BMP6 antibody (KY1070) either as monotherapy or in combination with Darbepoetin alfa on iron metabolism and anemia resolution in 2 different, well-established, and clinically relevant rodent models of ACD. In addition to counteracting hepcidin-driven iron limitation for erythropoiesis, we found that the combination of KY1070 and recombinant human EPO improved the erythroid response compared with either monotherapy in a qualitative and quantitative manner. Consequently, the combination of KY1070 and Darbepoetin alfa resulted in an EPO-sparing effect. Moreover, we found that suppression of hepcidin via KY1070 modulates ferroportin expression on erythroid precursor cells, thereby lowering potentially toxic-free intracellular iron levels and by accelerating erythroid output as reflected by increased maturation of erythrocyte progenitors. In summary, we conclude that treatment of ACD, as a highly complex disease, becomes more effective by a multifactorial therapeutic approach upon mobilization of endogenous iron deposits and stimulation of erythropoiesis.