The advantage of active immunotherapy
The advantage of active immunotherapy is long-term antibody production from short-term drug administration at limited cost. Conversely, immune response may be inconsistent or lacking, especially in older individuals, and adverse reactions—if immunologically based—may also be long-lasting. Initial experience with active vaccines was marred by an ill-fated trial of AN1792 (full-length Aβ42 with QS-21 adjuvant) that was halted following the occurrence of T cell–mediated meningoencephalitis in 6% of treated participants . Second-generation vaccines such as ACC-001 , , and CAD106 , have sought to generate anti-Aβ GSK 650394 restricted to the N-terminus, while avoiding T cell epitopes at the C-terminus , . CAD106 is the only vaccine to advance to phase 3 trials and has been selected for the Alzheimer Prevention Initiative ε4 homozygote study (; Identifier: ) . In contrast to active vaccination, passive immunization has the advantages of ensuring consistent antibody titers and allowing control of adverse events by stopping treatment. The major drawbacks of monoclonal antibodies (mAbs) are the need for repeated administrations and the associated cost of production . Over the past approximately 15 years several mAbs have been engineered to bind and clear Aβ () and have advanced to human trials (). Although the testing of mAbs has been fraught with failure and confusing results, the experience gained from these trials has provided important clues to enable the development of better treatments. Bapineuzumab Bapineuzumab (AAB-001; Pfizer Inc., New York, NY, and Janssen Pharmaceuticals, Inc., Raritan, NJ), a humanized immunoglobulin (Ig) G1 anti-Aβ mAb, binds the five N-terminal residues and clears both fibrillar and soluble Aβ. In 2000, Bard et al.(12) reported that in PDAPP transgenic mice, 3D6 (the murine precursor of bapineuzumab) entered the brain, decorated plaques, and induced the Fc receptor–mediated microglial phagocytosis of Aβ deposits. Bapineuzumab was the first mAb to enter human testing after termination of the AN1792 trial. In a phase 1 single ascending dose trial, 0.5, 1.5, or 5 mg/kg of bapineuzumab was generally safe and well tolerated in 30 participants with mild to moderate AD (13). However, 3 of 10 participants in the highest dose group developed magnetic resonance imaging (MRI) abnormalities consistent with vasogenic edema, all of which later resolved. Two participants were asymptomatic, and one experienced mild, transient confusion. These events prompted the Alzheimer’s Association Research Roundtable to convene a Workgroup in July 2010, which coined the term amyloid-related imaging abnormalities (ARIA) to refer to MRI signal alterations associated with Aβ-modifying therapies—specifically, ARIA-E to denote vasogenic edema/effusions and ARIA-H to indicate microhemorrhage and hemosiderosis (14). The subsequent phase 2 trial studied intravenous bapineuzumab (0.15, 0.5, 1.0, or 2.0 mg/kg) administered every 13 weeks for 78 weeks in mild to moderate AD (15). No significant treatment differences were found for the primary efficacy end points, Alzheimer’s Disease Assessment Scale–Cognitive Subscale [ADAS-Cog11] 16, 17 or Disability Assessment for Dementia (18), but prespecified exploratory analyses showed potential treatment differences for subjects who completed the study and APOE ε4 noncarriers. A parallel phase 2 study with [11C]-Pittsburgh compound B (11C-PiB) and positron emission tomography (PET) in 28 participants revealed some clearance of fibrillar Aβ (19). A retrospective review by two neuroradiologists of MRI scans from the phase 2 studies revealed that 36 participants (17%) had developed ARIA-E during bapineuzumab treatment, including 15 who were undetected during the trials. Of these participants, 28 (78%) reported no associated symptoms, whereas 8 symptomatic participants reported headache, confusion, and neuropsychiatric and gastrointestinal symptoms. Incident ARIA-H occurred in 17 (47%) of the participants with ARIA-E. Thirteen of 15 participants in whom ARIA-E was detected only retrospectively had received additional study infusions while ARIA-E was present, without any associated symptoms. ARIA-E was significantly related to higher doses of bapineuzumab and APOE ε4 status (20). The results of this retrospective analysis led to the practice of using central MRI readers to assess ARIA in later AD immunotherapy programs.