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Different strategies proposed as therapy for Alzheimer disease (AD) have aimed to reduce the level of toxic forms of A␤ peptide in the brain. Here, we directly analyze the therapeutic utility of the polyclonal anti-A␤ 1-11 antibody induced in 3xTg-AD mice vaccinated with the second generation prototype epitope vaccine. Substoichiometric concentrations of purified anti-A␤ 1-11 antibody prevented aggregation of A␤ 42 and induced disaggregation of preformed A␤ 42 fibrils down to nonfilamentous and nontoxic species. Anti-A␤ 1-11 antibody delayed A␤ 42 oligomer formation but ultimately appeared to stabilize nonfibrillar conformations, including oligomer-like assemblies. The reduced oligomer-mediated cytotoxicity observed upon preincubation of A␤ oligomers with the anti-A␤ 1-11 antibody in the absence of oligomer disaggregation suggests a possible oligomer rearrangement in the presence of the antibody. These in vitro observations suggest that preventive vaccination may protect from AD or may delay the onset of the disease, whereas therapeutic vaccination cannot disrupt the toxic oligomers and may only minimally alleviate preexisting AD pathology. AD4 is characterized by deposition of fibrillar forms of A␤ peptide in senile plaques, appearance of A␤ congophilic deposits and neurofibrillary tangles in the cerebrovasculature, and neuronal loss (1-4). A␤ peptide is cleaved from the amyloid precursor protein (APP) by ␤-and ␥-secretases (5-7) and is thought to play a central role in the onset and progression of AD (8 -10). In AD, the normally soluble A␤ molecule (39 -43 aa) undergoes conformational changes and is deposited as insoluble fibrils, oligomers, and protofibrills. Previously, it was demonstrated that A␤ neurotoxicity requires insoluble fibril formation (11) and that these fibrils serve as inducers of neuronal apoptosis (12). Recently, emphasis has shifted to smaller soluble oligomers of A␤ 42 , such as the 12-mers known as A␤-derived diffusible ligands, increased about 70-fold in AD patients' brains over controls (13). More recently, it was shown that extracellular accumulation of 56-kDa soluble A␤ assembly impairs memory in middle-aged APP/Tg 2576 mice in the absence of neuritic plaques (14). A␤ 42 dimers and trimers naturally secreted from a 7PA2 cell line were also suggested to be responsible for the disruption of cognitive functions (15). Importantly, intraventricular injection of such A␤ 42 small oligomers inhibited long term potentiation in rat hippocampus, and an injection of anti-A␤ monoclonal antibody 6E10 prevented this inhibition (16). It has also been demonstrated that passive immunization with monoclonal antibodies (NAB61) that specifically recognize a pathologic conformation present in A␤ oligomers resulted in a rapid improvement in spatial learning and memory (17).The therapeutic potency of polyclonal and monoclonal anti-A␤ antibodies was documented in different mouse models of AD (18 -25). Collectively, these data suggest that antibodies specific to the N-terminal region of A␤ are capable of reduci...

Recently, we reported that a DNA vaccine, composed of three copies of a self B cell epitope of amyloid-b (Ab 42 ) and the foreign T-cell epitope, Pan DR epitope (PADRE), generated strong anti-Ab immune responses in wild-type and amyloid precursor protein transgenic animals. Although DNA vaccines have several advantages over peptideprotein vaccines, they induce lower immune responses in large animals and humans compared with those in mice. The focus of this study was to further enhance anti-Ab 11 immune responses by developing an improved DNA vaccination protocol of the prime-boost regimen, in which the priming step would use DNA and the boosting step would use recombinant protein. Accordingly, we generated DNA and recombinant protein-based epitope vaccines and showed that priming with DNA followed by boosting with a homologous recombinant protein vaccine significantly increases the anti-Ab antibody responses and do not change the immunoglobulin G1 (IgG1) profile of humoral immune responses. Furthermore, the antibodies generated by this prime-boost regimen were long-lasting and possessed a higher avidity for binding with an Ab 42 peptide. Thus, we showed that a heterologous prime-boost regimen could be an effective protocol for developing a potent Alzheimer's disease (AD) vaccine.

Sulbactam-durlobactam is being developed for the treatment of infections caused by Acinetobacter baumannii, including those caused by multidrug- and carbapenem-resistant isolates. This was a phase 1 study to evaluate the effects of various degrees of renal impairment, including subjects with end-stage renal disease (ESRD) on hemodialysis (HD), on the pharmacokinetics and safety profile of durlobactam (also known as ETX2514) and sulbactam after single intravenous (i.v.) dose administration. For healthy subjects and those with mild or moderate renal impairment (RI), single 1,000-mg doses each of durlobactam and sulbactam via a 3-h i.v. infusion were administered, and for severe renal impairment, 500-mg doses were administered. For subjects with ESRD and HD, 500-mg i.v. doses each of durlobactam and sulbactam were administered post-HD and pre-HD, with a 1-week washout between doses. Among 34 subjects, decreasing renal function increased systemic exposure (peak plasma concentration [Cmax] and area under the concentration-time curve [AUC]) to durlobactam and sulbactam in a generally linear manner. In healthy subjects and in those with mild or moderate renal impairment, the majority of durlobactam and sulbactam was excreted in the urine, while approximately 40% or less was excreted in urine in subjects with severe renal impairment or ESRD. In subjects with ESRD, hemodialysis was effective at removing both durlobactam and sulbactam from plasma. Renal impairment had no effect of the safety/tolerability profile of durlobactam and sulbactam. In summary, RI and ESRD had a predictable effect on the pharmacokinetic (PK) profile of durlobactam and sulbactam with no adverse effects on the safety/tolerability profile. Durlobactam and sulbactam are cleared to a similar extent by renal elimination and are impacted similarly by renal impairment. The results from this study have been used with population PK modeling and nonclinically derived PK/PD (pharmacodynamic) exposure targets to establish dosage recommendations for durlobactam and sulbactam in patients with various degrees of RI. The dosing regimen of durlobactam-sulbactam will require adjustment in patients with severe renal insufficiency and in those with ESRD.