Passive Immunization in JNPL3 Transgenic Mice Using an Array of Phospho-Tau Specific Antibodies

Abstract

Recent work from our lab and few others have strongly suggested that immunotherapy could be an effective means of preventing the development of tau accumulation in JNPL3 transgenic mice, carrying the human P301L mutation. The aim of this study was to test the efficacy of a variety of specific tau monoclonal antibodies in JNPL3. Starting at 3 months of age, mice were treated for 4 months with weekly intraperitoneal injections of saline or purified tau monoclonal antibodies (10mg/Kg) different in specificity for pathological tau: CP13 (pSer202), RZ3 (pThr231) and PG5 (pSer409). As expected, not all the antibodies tested showed efficacy at preventing the development of tau pathology at the described dose, with some of them even worsening the pathological scenario. Only by targeting the pSer202 epitope with CP13 was a conspicuous reduction of insoluble or soluble tau in cortex and hindbrain obtained. Here we report about the importance of screening in vivo multiple tau antibodies in order to select the antibodies to direct into future clinical studies.

Tau Antibody Targeting Pathological Species Blocks Neuronal Uptake and Interneuron Propagation of Tau in Vitro

“…4 In one tau-transgenic mouse model, the phospho-tau antibodies specific to distinct phosphorylation sites affected tau pathology differently, with a certain phospho-tau antibody (PG5, pS409) even worsening the pathology. 13 It will be important to screen multiple phosphorylation sites in the same in vitro and/or in vivo assay to identify the most efficient therapeutic antibody.…”

Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls1

“…Finally, the importance of antibody charge for intracellular access has been well studied for potential cancer antibody therapies but not for tau antibodies or similar approaches targeting other amyloids. We have recently shown that antibody charge can robustly affect antibody uptake into neurons [19,64], which may explain why some labs detect tau antibodies inside neurons [2,7–9,11,12,14,39,40,65], whereas others do not for different antibodies [34,41,43]. This issue has particular importance for clinical trials because the humanized antibodies are likely to have a different charge than the mouse antibodies that they are based on.…”

“…Targeting numerous other epitopes has been shown to be effective in several studies. These include non-phosphorylated- [27,30,32,41,42,46–48,69,70], phosphorylated- [20,24,25,27,29,35,39,43,49], conformational-/oligomeric [20,31,33,34,40,44,45], and a truncated epitope [66,71]. Since these studies have various designs, they cannot be easily compared to identify the best epitopes to target.…”

“Tau immunotherapy: Hopes and hindrances”

“…So far, most of known abnormally phosphorylated states are detectable only at very late stages of hyperphosphorylation which seems that clearance is too late to retrieve neuronal function. 25,51 While there have been extensive attempts to neutralize tau toxicity employing mAbs removing different p-tau epitopes, only by targeting specific epitopes like pSer202, pSer413, pThr231 and pSer422 a decrease in insoluble/soluble tau in the brain was observable and the brain loss of function has been stopped in those mice models. 52 Furthermore, treatment with a phospho-tau peptide (containing the phosphorylated PHF-1 epitopes Ser 396 and Ser 404) in animal models prior to the onset of pathology has proven successful in preventing development of tau aggregates in the Tg P301L mouse tau model.…”