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<p>Alzheimer disease (AD) is the most common form of dementia affecting more than 6 million people in the United States. Currently, 3 monospecific antibodies targeting different Amyloid β (Aβ) species have been approved by the US FDA as disease modifying therapeutics for treatment in early AD patients with amyloid pathology. ABBV-916 is a clinical stage human IgG1 monoclonal antibody which binds to N-terminal truncated, pyroglutamate-modified at amino acid position 3, Aβ (Aβ<sub>pE3</sub>). The current study characterized ABBV-916 using human tissue samples and amyloid precursor protein (APP) transgenic mice. ABBV-916 selectively bound to recombinant Aβ<sub>pE3-42</sub> fibrils and native amyloid plaques in unfixed AD brain tissue but did not bind targets in human CSF. ABBV-916 significantly reduced dense plaques from brain tissue that were co-cultured with hiPSC-derived phagocytes. In APPPS1-21 mice, ABBV‑916 bound plaques in a dose-dependent manner after a single intravenous injection. In addition, three months of weekly administration of ABBV-916 murine surrogate antibody significantly decreased amyloid plaques in APPPS1-21 mice. <i>In vivo</i> two-photon imaging revealed that the murine version of ABBV-916 inhibited the growth of the plaques in APPPS1-21 mice. ABBV-916 murine surrogate antibody recruited microglia to plaques within 24-48 hours after a single intraperitoneal injection in Cx3cr1-tdTomato/APPPS1-21 mice. Importantly, in contrast to a positive control antibody, ABBV‑916 murine precursor antibody did not cause microhemorrhage in aged APPPS1-21 mice. Taken together, our results suggest that ABBV-916 is a promising drug candidate. Clinical testing is on-going to evaluate the plaque removal and safety profiles of ABBV-916 in AD patients.</p>

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Anti-pyroglutamate-3 Aβ immunotherapy engages microglia and inhibits amyloid accumulation in transgenic mouse models of Aβ amyloidosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月2日

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  • Fan Liao,
  • Maria Calvo-Rodriguez,
  • Meha Chhaya,
  • Julian P Sefrin,
  • Erik I Charych,
  • Mario Mezler,
  • Diana Clausznitzer,
  • Emily J McGlame,
  • Karen Zhao,
  • Allison Rodgers,
  • Yang Cao,
  • Philipp F Secker,
  • Laura Fernandez Garcia-Agudo,
  • Lili Huang,
  • Corinna Klein,
  • Tammy Dellovade,
  • Eric Karran

摘要

Alzheimer disease (AD) is the most common form of dementia affecting more than 6 million people in the United States. Currently, 3 monospecific antibodies targeting different Amyloid β (Aβ) species have been approved by the US FDA as disease modifying therapeutics for treatment in early AD patients with amyloid pathology. ABBV-916 is a clinical stage human IgG1 monoclonal antibody which binds to N-terminal truncated, pyroglutamate-modified at amino acid position 3, Aβ (AβpE3). The current study characterized ABBV-916 using human tissue samples and amyloid precursor protein (APP) transgenic mice. ABBV-916 selectively bound to recombinant AβpE3-42 fibrils and native amyloid plaques in unfixed AD brain tissue but did not bind targets in human CSF. ABBV-916 significantly reduced dense plaques from brain tissue that were co-cultured with hiPSC-derived phagocytes. In APPPS1-21 mice, ABBV‑916 bound plaques in a dose-dependent manner after a single intravenous injection. In addition, three months of weekly administration of ABBV-916 murine surrogate antibody significantly decreased amyloid plaques in APPPS1-21 mice. In vivo two-photon imaging revealed that the murine version of ABBV-916 inhibited the growth of the plaques in APPPS1-21 mice. ABBV-916 murine surrogate antibody recruited microglia to plaques within 24-48 hours after a single intraperitoneal injection in Cx3cr1-tdTomato/APPPS1-21 mice. Importantly, in contrast to a positive control antibody, ABBV‑916 murine precursor antibody did not cause microhemorrhage in aged APPPS1-21 mice. Taken together, our results suggest that ABBV-916 is a promising drug candidate. Clinical testing is on-going to evaluate the plaque removal and safety profiles of ABBV-916 in AD patients.