Anti-tau and Anti-Alpha-Synuclein Antibodies Derived from Llama

Inventor:

Einar Sigurdsson, Ph.D.
Neuroscience Institute
Professor, Department of Neuroscience and Physiology
Professor, Department of Psychiatry

Background:

Several tau and alpha-synuclein immunotherapies have advanced to clinical trials, with all the passive approaches using whole antibodies. Single domain antibody fragments (sdAbs), which are ten times smaller than antibodies, have not been well studied. However, their distinct properties provide certain advantages that justify exploring their therapeutic and diagnostic potential. It is hypothesized that their small size will provide unique benefits over the larger whole antibodies, primarily because of greater access into the brain and to their protein target, and to some extent due to their binding to novel epitopes. Various pathways are involved in antibody-mediated clearance of pathological tau or alpha-synuclein proteins, and the importance of each depends on the antibody and its size. With regard to diagnosis, tau imaging probes that are currently in clinical trials are beta-sheet dyes that are not specific for tau and cannot detect all tauopathies. Specific or selective small molecule alpha synuclein imaging probes have not been described in the literature. sdAbs have several advantages as potential imaging agents, such as specificity for tau or alpha-synuclein, small size, excellent tissue penetration, ability to bind hidden epitopes, high affinity, and they are easy to engineer, which also are advantageous for their therapeutic applications. However, the published results from the group clearly show in various models, including animals, that the ideal binding profile of antibodies differs for therapeutic vs. diagnostic candidates. NYU inventor Dr. Einar Sigurdsson has pioneered targeting the tau protein with immunotherapy, and published the first report on the in vivo imaging diagnostic potential of anti-tau single chain variable antibody fragments (scFvs). The findings have been confirmed and extended by multiple groups, leading to eight clinical trials on tau immunotherapy with several additional trials likely to commence in the near future. The Sigurdsson Lab has now identified about 50 anti-tau single domain antibody (sdAb) clones and a similar number of anti-alpha-synuclein sdAb clones with varying binding properties to different forms of tau and alpha-synuclein that have unique sequences of their binding regions (CDRs). The sdAbs were selected based on their tau and alpha-synuclein binding properties from a phage display library generated from peripheral blood mononuclear cells of llamas immunized with tau or alpha-synuclein immunogens, respectively.

Advantages:

  •  Single domain antibody fragments (sdAbs), which are ten times smaller thanantibodies, will provide unique therapeutic and diagnostic benefits over the larger whole antibodies.
  • Greater access into the brain and to their protein target.
  • Can bind to novel cryptic epitopes that the larger antibodies cannot access.
  •  They are also easier to scale up and engineer than scFvs.

Potential Application:

  •  Therapies and diagnostic probes for all tauopathies and alpha-synucleinopathies

Contact: 

Sadhana Chitale, Ph.D.

Director Life Science

sadhana.chitale@nyulangone.org