IBC‐Ab002, an anti‐PD‐L1 monoclonal antibody tailored for treating Alzheimer’s disease Nonhuman/Lead optimization studies

• Published in: Alzheimer's & dementia Vol. 16; no. S9
• Main Authors: Baruch, Kuti, Kertser, Alexander, Matalon, Omri, Forsht, Ofir, Braiman, Shai, Shochat, Eliezer, David, Carol, Yoles, Eti
• Format: Journal Article
• Language: English
• Published: 01.12.2020
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.042978

Abstract Background The ongoing cross‐talk between the immune system and the central nervous system plays a major role in healthy brain tissue maintenance, with critical implications to brain aging and neurodegeneration. Based on the innovative concept of “protective autoimmunity”, established by Schwartz and her group, it was shown that targeting the programmed cell death receptor (PD)‐1 / PD‐L1 pathway evokes an immune response that supports recruitment of specialized immune cells (primarily of myeloid origin) to the brain territory, where these cells act by enhancing clearance of toxic elements, improving neuronal function, and reducing inflammation in mouse models of Alzheimer's disease (AD) and dementia. Maintaining a long‐lasting effect was found to be dependent on intermittent treatment course. IBC‐Ab002 is a novel fully human anti‐PD‐L1 monoclonal antibody that was designed, by point mutations on its Fc backbone, to fulfil the pharmacokinetics (PK), pharmacodynamics (PD) and safety characteristics anticipated for treating AD. Antibody optimization and lead selection will be presented. Methods Correlation between PK, PD, and antibody efficacy and safety, was evaluated using different antibody variants that share the same variable region, but differ in their physical properties due to point mutations in their Fc region. These studies, in mouse models of AD and in healthy cynomolgus monkeys, were used for modeling human PK/PD properties of IBC‐Ab002. Results Pharmacological studies in mice revealed that treatment efficacy is primarily Cmax‐dependent, rather than exposure‐dependent. Biomarkers for biological activity were identified in the blood of both treated mice and monkeys, and PK/PD relationships were used to predict IBC‐Ab002 PK and effective dose range in humans. The ability to maintain treatment efficacy using intermittent administration regimen was evaluated in a longitudinal study, and found to be effective for up to 6 months from treatment initiation. Using a mouse model that spontaneously develops autoimmune diabetes, we also show that the chosen antibody modifications significantly improve its safety profile. Conclusions IBC‐Ab002 antibody was selected for clinical development based on its unique characteristics, tailored for the mechanism of action intended for treating AD, and superior safety profile in terms of immune‐related adverse events. We are currently planning the first‐in‐human study of IBC‐Ab002 in AD patients.