Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab

Abstract

Background: Gantenerumab is a fully human anti-A␤ monoclonal antibody in clinical development for the treatment of Alzheimer disease (AD). Objectives: To investigate whether treatment with gantenerumab leads to a measurable reduction in the level of A␤ amyloid in the brain and to elucidate the mechanism of amyloid reduction. Design: A multicenter, randomized, double-blind, placebo-controlled, ascending-dose positron emission tomographic study. Additionally, ex vivo studies of human brain slices from an independent sample of patients who had AD were performed.

First Administration of the Fc-Attenuated Anti-β Amyloid Antibody GSK933776 to Patients with Mild Alzheimer’s Disease: A Randomized, Placebo-Controlled Study

“…The lack of ARIA-E in this study provides support for the hypothesis that this adverse effect occurs as a result of an Fc-mediated inflammatory response to wild-type anti-Aβ mAb. Our findings are in contrast with those obtained with anti-Aβ mAbs bapineuzumab and gantenerumab, which are known to cause ARIA-E [ 2 , 6 , 9 ]. The studies of bapineuzumab and gantenerumab also reported a positive association between ARIA-E and APOE ε4 carrier status, and in phase III studies of bapineuzumab and solanezumab significant numbers of APOE ε4 noncarriers were amyloid PET negative and may have been misdiagnosed [ 9 , 18 ].…”

First Administration of the Fc-Attenuated Anti-β Amyloid Antibody GSK933776 to Patients with Mild Alzheimer’s Disease: A Randomized, Placebo-Controlled Study

“…The lack of ARIA-E in this study provides support for the hypothesis that this adverse effect occurs as a result of an Fc-mediated inflammatory response to wild-type anti-Aβ mAb. Our findings are in contrast with those obtained with anti-Aβ mAbs bapineuzumab and gantenerumab, which are known to cause ARIA-E [ 2 , 6 , 9 ]. The studies of bapineuzumab and gantenerumab also reported a positive association between ARIA-E and APOE ε4 carrier status, and in phase III studies of bapineuzumab and solanezumab significant numbers of APOE ε4 noncarriers were amyloid PET negative and may have been misdiagnosed [ 9 , 18 ].…”

An Effector-Reduced Anti- -Amyloid (A ) Antibody with Unique A Binding Properties Promotes Neuroprotection and Glial Engulfment of A

“…Together, the reduced effector function of MABT, a humanized anti-A␤ IgG4 antibody, and its unique A␤ binding profile exclusively position this anti-A␤ immunotherapy candidate to test both mechanisms of efficacy and safety in the clinic. Indeed, phase I data presented in this report are consistent with this hypothesis, showing that, at dose levels and exposure Ͼ10-fold compared with other anti-A␤ mAbs on human IgG1 backbones (Salloway et al, 2009;Ostrowitzki et al, 2012), MABT showed no signs of vasogenic edema. Interestingly, however, solanezumab is also on a human IgG1 backbone, but has not shown the same level of vasogenic edema as other human IgG1 anti-A␤ antibodies (Carlson et al, 2011).…”

Gantenerumab: A Novel Human Anti-Aβ Antibody Demonstrates Sustained Cerebral Amyloid-β Binding and Elicits Cell-Mediated Removal of Human Amyloid-β

“…Notably, the minimal gantenerumab concentration to initiate A␤ clearance was 0.07 nM, i.e., the same concentration that was effective to yield significant A␤ plaque binding as measured by immunostaining. Similar results were obtained with primary human microglia cells [32] further supporting the hypothesis of Fc receptor/microgliamediated phagocytosis and lysosomal degradation. Cellular phagocytosis was previously reported with murine anti-A␤ antibodies applied to transgenic mouse brain sections at 10 g/mL (∼70 nM) and cultured with primary murine microglia cells [10].…”

First Administration of the Fc-Attenuated Anti-β Amyloid Antibody GSK933776 to Patients with Mild Alzheimer’s Disease: A Randomized, Placebo-Controlled Study

“…The lack of ARIA-E in this study provides support for the hypothesis that this adverse effect occurs as a result of an Fc-mediated inflammatory response to wild-type anti-Aβ mAb. Our findings are in contrast with those obtained with anti-Aβ mAbs bapineuzumab and gantenerumab, which are known to cause ARIA-E [ 2 , 6 , 9 ]. The studies of bapineuzumab and gantenerumab also reported a positive association between ARIA-E and APOE ε4 carrier status, and in phase III studies of bapineuzumab and solanezumab significant numbers of APOE ε4 noncarriers were amyloid PET negative and may have been misdiagnosed [ 9 , 18 ].…”

An Effector-Reduced Anti- -Amyloid (A ) Antibody with Unique A Binding Properties Promotes Neuroprotection and Glial Engulfment of A

“…Together, the reduced effector function of MABT, a humanized anti-A␤ IgG4 antibody, and its unique A␤ binding profile exclusively position this anti-A␤ immunotherapy candidate to test both mechanisms of efficacy and safety in the clinic. Indeed, phase I data presented in this report are consistent with this hypothesis, showing that, at dose levels and exposure Ͼ10-fold compared with other anti-A␤ mAbs on human IgG1 backbones (Salloway et al, 2009;Ostrowitzki et al, 2012), MABT showed no signs of vasogenic edema. Interestingly, however, solanezumab is also on a human IgG1 backbone, but has not shown the same level of vasogenic edema as other human IgG1 anti-A␤ antibodies (Carlson et al, 2011).…”

Gantenerumab: A Novel Human Anti-Aβ Antibody Demonstrates Sustained Cerebral Amyloid-β Binding and Elicits Cell-Mediated Removal of Human Amyloid-β

“…Notably, the minimal gantenerumab concentration to initiate A␤ clearance was 0.07 nM, i.e., the same concentration that was effective to yield significant A␤ plaque binding as measured by immunostaining. Similar results were obtained with primary human microglia cells [32] further supporting the hypothesis of Fc receptor/microgliamediated phagocytosis and lysosomal degradation. Cellular phagocytosis was previously reported with murine anti-A␤ antibodies applied to transgenic mouse brain sections at 10 g/mL (∼70 nM) and cultured with primary murine microglia cells [10].…”

First Administration of the Fc-Attenuated Anti-β Amyloid Antibody GSK933776 to Patients with Mild Alzheimer’s Disease: A Randomized, Placebo-Controlled Study

“…The lack of ARIA-E in this study provides support for the hypothesis that this adverse effect occurs as a result of an Fc-mediated inflammatory response to wild-type anti-Aβ mAb. Our findings are in contrast with those obtained with anti-Aβ mAbs bapineuzumab and gantenerumab, which are known to cause ARIA-E [ 2 , 6 , 9 ]. The studies of bapineuzumab and gantenerumab also reported a positive association between ARIA-E and APOE ε4 carrier status, and in phase III studies of bapineuzumab and solanezumab significant numbers of APOE ε4 noncarriers were amyloid PET negative and may have been misdiagnosed [ 9 , 18 ].…”

An Effector-Reduced Anti- -Amyloid (A ) Antibody with Unique A Binding Properties Promotes Neuroprotection and Glial Engulfment of A

“…Together, the reduced effector function of MABT, a humanized anti-A␤ IgG4 antibody, and its unique A␤ binding profile exclusively position this anti-A␤ immunotherapy candidate to test both mechanisms of efficacy and safety in the clinic. Indeed, phase I data presented in this report are consistent with this hypothesis, showing that, at dose levels and exposure Ͼ10-fold compared with other anti-A␤ mAbs on human IgG1 backbones (Salloway et al, 2009;Ostrowitzki et al, 2012), MABT showed no signs of vasogenic edema. Interestingly, however, solanezumab is also on a human IgG1 backbone, but has not shown the same level of vasogenic edema as other human IgG1 anti-A␤ antibodies (Carlson et al, 2011).…”

Gantenerumab: A Novel Human Anti-Aβ Antibody Demonstrates Sustained Cerebral Amyloid-β Binding and Elicits Cell-Mediated Removal of Human Amyloid-β

“…Notably, the minimal gantenerumab concentration to initiate A␤ clearance was 0.07 nM, i.e., the same concentration that was effective to yield significant A␤ plaque binding as measured by immunostaining. Similar results were obtained with primary human microglia cells [32] further supporting the hypothesis of Fc receptor/microgliamediated phagocytosis and lysosomal degradation. Cellular phagocytosis was previously reported with murine anti-A␤ antibodies applied to transgenic mouse brain sections at 10 g/mL (∼70 nM) and cultured with primary murine microglia cells [10].…”