Date: 2017-08-29
Type of
information: Publication of results in a medical journal
phase: preclinical
Announcement: publication of results in the Journal of Biological Chemistry
Company: Probiodrug (Germany)
Product: PBD-C06
Action
mechanism:
- monoclonal antibody. PBD-C06 is a pGlu-Abeta-specific monoclonal antibody. This humanized and deimmunized monoclonal antibody has been selected based on an optimal safety and pharmacological profile. CMC development for PBD-C06 has been initiated.
Disease: Alzheimer's disease
Therapeutic
area: Neurodegenerative diseases
Country:
Trial
details:
Latest
news:
- • On August 29, 2017, Probiodrug announced 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.
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.
- Amyloid-beta (Abeta) aggregate-clearing by the murine anti-pyroglutamate-3 Abeta IgG2a monoclonal antibody PBD-C06 with and without a complement mutation in an Alzheimer’s mouse model
- • On November 16, 2016, Probiodrug announced the first results of a preclinical study in an AD mouse model with the pyroglutamate-3 Abeta (pGlu3-Abeta)-specific antibody mPBD-C06, comparing versions with and without a mutation eliminating complement activation which have been presented as a poster at the Society for Neuroscience (SfN) meeting on 16 November 2016 in San Diego. Data were generated in collaboration with Cynthia Lemere of Brigham and Women’s Hospital, Harvard Medical School, and QPS, Graz, Austria.
- Previously, Lemere’s team showed that the mouse IgG2a variant of the anti-pGlu3-Abeta monoclonal antibody was more effective at clearing Abeta aggregates and rescued behavioral deficits compared to the mouse IgG1 version (SfN 2015). In the present study, the effect of eliminating the antibody’s ability to activate complement (CDC) on the efficiency to reduce Abeta plaques was investigated and it was found that both variants - with and without CDC - reduced pGlu3-Abeta as well as general Abeta to the same extent - without inducing microhemorrhages. Thus, avoiding complement activation did not impact the capacity of mPBD-C06 to eliminate pGlu3-Abeta aggregates. In addition, microglial activation was assessed in vivo by 18F-GE180 TSPO microPET imaging at baseline and following a single injection of the pGlu3-Abeta antibody variants. In contrast to the IgG2a variant, which showed enhanced whole brain uptake of 18F-GE180 in AD mice, the antibody lacking CDC did not alter the TSPO signal after injection.
- In summary, the data demonstrate for the first time, that microglial activation, analyzed by TSPO microPET, can be reduced by CDC inactivation without impairing the potency of the antibody to clear amyloid deposits. Further studies are underway to better understand the clearance mechanisms for each of these anti-pGlu3 Abeta antibodies.
Is
general: Yes
