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TABLE OF CONTENTS
2.6.3 薬理試験概要表 ... 2
2.6.3.1 薬理試験 ... 2
2.6.3.2 効力を裏付ける試験 ... 3
2.6.3.3 副次的薬理試験 ... 4
2.6.3.4 安全性薬理試験 ... 5
2.6.3.5 薬力学的薬物相互作用試験 ... 5
2.6.3 薬理試験概要表 2.6.3.1 薬理試験
Overview Test Article: ALXN1210 (Ravulizumab)
Type of Study Test System Method of
Administration Testing Facility Study Number Location (eCTD)*
Primary Pharmacodynamics
An in vitro assessment of the effects of pH on the kinetics of
ALXN1210 and eculizumab binding to human C5 and FcRn Surface plasmon
resonance In vitro Alexion
Pharmaceuticals RTR-0003v1.0 5.3.2.3.1 Epitope mapping of the ALXN1210 binding site on human C5
and predicted cross-reactivity of ALXN1210 with non-human C5
Surface plasmon resonance,
complement-mediated hemolysis assays, in silico amino acid sequence comparisons
In vitro Alexion
Pharmaceuticals RTR-0006v1.0 4.2.1.1.1
A comparison of single dose pharmacokinetics and pharmacodynamics of two anti-human C5 monoclonal antibodies, ALXN1210 and eculizumab, in the presence and absence of human C5 in NOD-scid mice
NOD-scid mice Intravenous Alexion
Pharmaceuticals RTR-0008v1.0 4.2.2.7.2
Secondary Pharmacodynamics
A comparative assessment of ALXN1210, eculizumab and
h5G1.1-IgG1 binding to Fc-gamma receptors and C1q in vitro ELISA, surface plasmon resonance and biolayer interferometry
In vitro Alexion
Pharmaceuticals RTR-0005v1.0 5.3.2.3.2 Safety Pharmacology No studies performed Not applicable Not applicable Not applicable Not applicable Pharmacodynamic Drug Interactions No studies performed Not applicable Not applicable Not applicable Not applicable * Ravulizumab eCTD for PNH indication (eCTD No. 300904001)
2.6.3.2 効力を裏付ける試験
Test Article: ALXN1210 (Ravulizumab) Type of Study Species/Strain Method of
Admin. Doses
(μg/kg) Gender and No. per Group
Noteworthy Findings Study Number
An in vitro assessment of the effects of pH on the kinetics of ALXN1210 and eculizumab binding to human C5 and FcRn
Human In vitro NA NA Two amino acid substitutions in the complementarity- determining regions (Y27H and S57H) decrease the affinity of ALXN1210 for human C5 by ~ 17-fold at pH 7.4 and ~36-fold at pH 6.0, compared to eculizumab.
Two amino acid substitutions in the heavy chain constant region (M428L and N434S) increase the affinity of ALXN1210 for FcRn by ~10-fold compared to eculizumab. Together, these substitutions were expected to significantly attenuate target-mediated drug disposition and increase the fraction of antibody recycled from the early endosome back into the vascular compartment.
RTR-0003 v1.0
Epitope mapping of the ALXN1210 binding site on human C5 and predicted cross-reactivity of ALXN1210 with non-human C5
Human, various non-human primate, various non-primate mammalian species
In vitro NA NA Four residues in the MG7 domain of human C5,
including W917, were demonstrated to be critical for ALXN1210 binding and activity. ALXN1210 did not block in vitro hemolytic activity of sera from any animal species tested. The results suggest that ALXN1210 binding to non-human C5 is insufficient to study the toxicology, pharmacokinetics and pharmacodynamics of ALXN1210 in any animal species tested.
RTR-0006 v1.0
Comparison of single dose pharmacokinetics and pharmacodynamics of two anti-human C5 monoclonal antibodies, ALXN1210 and eculizumab, in the presence and absence of human C5 in NOD-scid mice
Mouse/NOD-scid IV for Abs, SC for hC5
250 μg of hC5 loading dose on day −1, followed by 50 μg twice daily
Females;
8/group ALXN1210 had a significantly longer half-life than eculizumab in this mouse model. The extended exposure of ALXN1210 corresponded to extended duration of pharmacodynamic effect relative to eculizumab.
RTR-0008 v1.0
Abbreviations: Ab = antibody, ELISA = enzyme-linked immunosorbent assay, FcRN = Fc receptor, hC5 = human C5, IV = intravenous, NA = not applicable, NOD-scid = non-obese diabetic/severe combined immunodeficient, SC = subcutaneous
2.6.3.3 副次的薬理試験
Test Article: ALXN1210 (Ravulizumab) Type of Study Species/Strain Method of
Admin. Doses
(μg/kg) Gender and No. per Group
Noteworthy Findings Study Number
A comparative assessment of ALXN1210,
eculizumab and
h5G1.1-IgG1 binding to Fc-gamma receptors and C1q in vitro
Human In vitro NA NA ALXN1210 displayed no detectable binding to FcγRI, FcγRIIb/c, FcγRIIIa, or FcγRIIIb, and a ~3-fold weaker association with FcγRIIa than an IgG1 isotype control.
In addition, no interactions between ALXN1210 and C1q were detected. The results are consistent with the hypothesis that ALXN1210 has little to no capacity to elicit effector function through FcγRs or C1q to mediate ADCC or CDC, respectively.
RTR-0005 v1.0
Abbreviations: ADCC = antibody-dependent cell-mediated cytotoxicity, CDC = complement-dependent cytotoxicity, FcγR = Fc-gamma receptors, NA = not applicable