Treatment with recombinant human bone morphogenetic protein 7 leads to a transient induction of neutralizing autoantibodies in a subset of patients.
BACKGROUND
Recombinant human bone morphogenetic protein 7 (rhBMP7) is applied for treatment of bone fractures, especially tibial non-unions. Its application may induce autoantibodies (aAB) affecting the targeted and endogenous signaling pathways and in turn negatively impact treatment efficacy.


METHODS
Novel and sensitive assays for the quantification of BMP7-aAB and BMP2-aAB were established and used to analyze serum samples from healthy controls (n = 100 men, n = 100 women) and patients with long bone fracture (n = 265) treated or not with rhBMP7. Sera from three to nine time points per patient were available and enabled the evaluation of aAB over a time course of up to one year. Functional activity of the BMP-aAB was tested with a BMP-responsive cell-based reporter assay. Consolidation of the fracture was evaluated as clinical outcome potentially affected by BMP7-aAB.


RESULTS
Prevalence of BMP7-aAB and BMP2-aAB was 1-2.5% in non-treated patients or healthy controls. The rhBMP7 treatment induced a transient increase in BMP7-aAB in a subset of patients, returning to non-detectable levels within six months. IgG from BMP7-aAB positive sera inhibited dose dependently the BMP7-reporter gene activity, whereas control sera were without effect. Successful consolidation of the fracture was observed in the majority of both aAB-positive and aAB-negative patients.


CONCLUSIONS
We conclude that BMP7-aAB can be detected as natural aAB in healthy subjects, and are transiently induced by rhBMP7 therapy in a subset of patients. The aAB are capable of antagonizing BMP7 signaling in vitro, but do not preclude treatment success in patients.
Institute for Experimental Endocrinology, Charité - Universitätsmedizin Berlin, D-13353 Berlin, Germany.
Andrea
A
Schuette
Department of Orthopedics and Trauma Surgery, Heidelberg University Hospital, D-69118 Heidelberg, Germany.
Arash
A
Moghaddam
Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, D-13353 Berlin, Germany.
Petra
P
Seemann
Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, D-13353 Berlin, Germany; Julius Wolff Institute, Charité - Universitätsmedizin Berlin, D-13353 Berlin, Germany.
Georg N
GN
Duda
Department of Orthopedics and Trauma Surgery, Heidelberg University Hospital, D-69118 Heidelberg, Germany.
Gerhard
G
Schmidmaier
Institute for Experimental Endocrinology, Charité - Universitätsmedizin Berlin, D-13353 Berlin, Germany.
Lutz
L
Schomburg
Autoimmunity; Biologicals; Bone morphogenetic protein; Consolidation; Fracture; Growth factor