Unique binding mode of PBD-C06 to pGlu-Abeta peptides identified
Published: 29.08.17
Probiodrug publishes mechanism of target binding for its lead anti-pGlu-Abeta monoclonal antibody PBD-C06
HALLE (SAALE), Germany, 29 August 2017 – Probiodrug AG (Euronext Amsterdam: PBD), a biopharmaceutical company developing novel therapeutic solutions to treat Alzheimer’s disease (AD), announced today that results from a collaboration between Probiodrug, the Fraunhofer Institute for Cell Therapy and Immunology (IZI), Department of Drug Design and Target Validation (IZI-MWT, HalleS.) and a team led by Dr. Milton T. Stubbs at the Martin-Luther-Universität Halle-Wittenberg (MLU) were published in the Journal of Biological Chemistry (Piechotta et al,. J. Biol. Chem. 2017 292:12713). In these studies, the binding characteristics of a murine version of Probiodrug’s lead therapeutic antibody (PBD-C06) against its designated target pGlu-Abeta was analyzed at the molecular level applying co-crystallization and X-ray structure analysis. The studies revealed a unique binding mode of PBD-C06 to pGlu-Abeta peptides, which are believed to catalyze the seeding of synapto/neurotoxic Abeta oligomers, a key culprit in the pathology of AD. Furthermore, the data provide a rationale for the high target specificity of PBD-C06 and suggest low binding to off-targets, such as unmodified, less toxic Abeta peptides.
These insights reveal a differentiating biological property of PBD-C06 compared to other anti-Abeta antibodies and further support the development of PBD-C06. PBD-C06 is a humanized and deimmunized monoclonal antibody selected based on an optimal safety and pharmacological profile. CMC development for PBD-C06 has been initiated.
Prof. Dr. Milton T. Stubbs from the Institute for Biochemistry und Biotechnology at the MLU commented: “The results explain why the unique structure of pGlu-Abeta can facilitate enhanced aggregation of Abeta oligomers. Specific targeting of pGlu-Abeta with antibodies could eliminate neurotoxic pGlu-Abeta containing oligomers in the brain. PBD-C06 thus has a promising therapeutic potential”.
Dr. Inge Lues, PBD’s Chief Development Officer, added: “These results provide differentiating insights into the biology of PBD-C06, allowing a better understanding of how PBD-C06 interacts with its target at the molecular level. Importantly, they support the nomination of PBD-C06 as an optimal candidate for further development.
Probiodrug is progressing two complementary strategies for tackling pGlu-Abeta with two candidates in development: PQ912, a small molecule inhibitor of Glutaminyl Cyclase, now in Phase 2, and PBD-C06, a pGlu-Abeta-specific monoclonal antibody in preclinical stage.