. Immunotherapy is one of the most promising approaches for treatment of various human diseases including cancers, autoimmune and infectious diseases. However, systemic immunotherapies have been ineffective for central nervous system (CNS) disorders because the blood-brain barrier (BBB) limits their delivery to the brain. Development of new antibody agents able to overcome the BBB is a new frontier of immunotherapy. One strategy is to use receptor-mediated transport to deliver biologics across the BBB. Abzyme proposes to use its proprietary SDALib platform for rapid generation of antibodies to receptors present in the CNS, and its Abz2 technology for reformatting traditional antibodies to create bispecific antibodies that can overcome the BBB via receptor-mediated transcytosis and binding its specific target in the brain. Using Abzyme's SDALib platform, camelid single domain antibodies against human transferrin receptor (TfR) have already been developed and generation of VHH antibodies to leptin receptor (LepR) is in progress. In addition, a set of 15 murine monoclonal antibodies against human protein targets of diagnostic and therapeutic significance is in our possession. The focus of Phase I is to demonstrate the feasibility of rapidly transforming disease-specific traditional antibodies into IgG-like bispecific antibodies, preserving antibody Fc effector functions and antibody binding affinity, and the ability of the newly obtained bispecifics to cross the BBB. Specifically, bispecific recombinant antibodies with one arm targeting HER2 or EGFR and another arm against TfR or LepR will be developed. Demonstration of the robustness of bispecific antibody production and BBB penetration in cell-based BBB models and small animals will be the basis for Phase II application submission. Phase II work focus includes: (i) obtaining the preclinical in vivo therapeutic efficacy, pharmacodynamics, pharmacokinetics and toxicity data for antibodies developed in Phase I that are necessary for submission of an IND; (ii) using the SDALib antibody generation platform and Abz2 bispecific approach to produce of a suite of BBB- penetrating antibodies relevant to CNS disorders. 2

Public Health Relevance

Immunotherapy targeting cell surface and extracellular proteins is one of the most promising approaches for treatment of various human diseases but has yet to be applied to central nervous system disorders due to the blood-brain barrier. As a result of this project, a suite of novel IgG-like bispecific antibodies capable of overcoming the BBB will be produced for treatment of various CNS disorders. 3

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1)
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Fertig, Stephanie
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Abzyme Therapeutics, LLC
United States
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