A step forward with MultiTEP
Alzheimer’s vaccine targeted against pathological Tau protein generates significant antibodies in mice
HUNTINGTON BEACH, Calif.—Between the mental, medical and emotional impact of Alzheimer’s disease—for both patients and loved ones—a way to combat this neurodegenerative disease is arguably one of the most sought-after treatments. Researchers have targeted elements of Alzheimer’s disease in various combinations, from beta amyloid production to neurofibrillary tangles, in hopes of developing a cure, but success has remained elusive.
But what about heading the disease off at the pass—a vaccine, rather than a cure?
That approach is bearing some fruit of late. Capo Therapeutics Inc. recently reported on strong preclinical data for an Alzheimer’s disease (AD) tau vaccine. The vaccine was created by researchers from the Institute for Molecular Medicine (IMM) and collaborators at the University of California, Irvine, and is being commercialized by Capo Therapeutics, which secured the patent to the MultiTEP technology in 2018. Preclinical data demonstrating the vaccine’s effectiveness in mice was published in late October in Scientific Reports under the title “A MultiTEP platform-based epitope vaccine targeting the phosphatase activating domain (PAD) of tau: therapeutic efficacy in PS19 mice.”
Dr. Armine Hovakimyan, associate professor at IMM and the lead author, said, “For a vaccine to be effective, it has to induce therapeutically potent levels of antibodies—which our anti-Tau vaccine achieved. Importantly, MultiTEP platform-based vaccines do not induce potentially harmful autoreactive T helper cell responses, while still generating antibodies that bind strongly to pathological forms of Tau in human brain tissue from AD cases.”
“The MultiTEP technology is a third-generation platform technology that generates very high levels of antibodies; the antibodies are specific to the antigen of interest and there are none detectable to the carrier, does not activate harmful auto-reactive T cells, and activates memory T cells. We believe that there is no other active vaccine platform that can achieve these four key elements and are excited about future clinical trials,” added Dr. Harry Lander, CEO of Capo Therapeutics.
The vaccine in question specifically targets only the pathological Tau protein associated with Alzheimer’s disease, not the normal version of the protein. In addition, the vaccine generates high titers of antibodies, and in mouse models of taupathy and Alzheimer’s disease, it led to a reduction in Tau aggregate in the brain and improvements in behavioral and motor defects, respectively. While beta amyloid has been the most popular target in Alzheimer’s disease treatment efforts to date, the authors note that “although levels of Aβ oligomers correlate with disease severity, tau pathology more strongly correlates with the progression of AD ... Although both soluble and fibrillar tau may contribute to neuronal and synaptic dysfunction and loss, growing evidence suggests that soluble tau oligomers are the more toxic form and the accumulation of oligomers at the synapse may be critical for neurodegeneration.”
“Because only a small percentage (0.1 percent) of circulating antibodies can enter the brain, for neurodegenerative diseases it is necessary to generate very high levels of antibody in the periphery so that enough can cross the blood-brain barrier and have an effect,” Lander tells DDNews. “Another shortcoming of prior-generation vaccines is that they generated antibodies to the carrier, rather than the molecule of interest, thus removing antigen from the body and reducing its immunogenicity. MultiTEP is designed to overcome this and, in fact, there are no detectable antibodies to MultiTEP in vaccinated monkeys so we expect similar results in our clinical trials.”
“Another issue to overcome is to make sure we don’t create an immune response that attacks our own normal tissue. We solved this by having the right B cell epitope and ensuring a balanced Th1/Th2 response. Finally, since the population of those with Alzheimer’s is greater than 60 years old, we had to make sure that these people’s immune systems—which don’t have too many naïve T cells, but do have many memory T cells—are appropriately stimulated,” he adds.
Lander does not discount the beta amyloid approach, remarking that “There is now a glimmer of hope that targeting Aβ can indeed prevent or delay the disease based on Biogen’s human monoclonal antibody, aducanumab.” In fact, he opines that a combination of both approaches will be the most effective: “We certainly believe we will slow the progression of the disease with our Aβ vaccine, and perhaps prevent it. Ideally, we would couple this preventive treatment with an anti-Tau vaccine as well as anti-inflammatory treatment to cover the preventive and therapeutic spectra.”
The next step, according to Lander, is a clinical trial featuring a DNA vaccine of anti-Aβ-MultiTEP (AV-1959D), with a start date of 2020.
“This study will tell us about the safety and immunogenicity of this vaccine,” he says. “We are also in the process of cGMP manufacturing our protein vaccine anti-Tau-MultiTEP (AV-1980R/A) for IND-enabling studies in preparation for clinical trials in 2022.”