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Development of the clinical candidate PBD-C06, a humanized pGlu3-Aβ-specific antibody against Alzheimer's disease with reduced complement activation

: Hettmann, Thore; Gillies, Stephen D.; Kleinschmidt, Martin; Piechotta, Anke; Makioka, Koki; Lemere, Cynthia A.; Schilling, Stephan; Rahfeld, Jens-Ulrich; Lues, Inge

Volltext ()

Scientific Reports 10 (2020), Nr.1, Art. 3294, 13 S.
ISSN: 2045-2322
Zeitschriftenaufsatz, Elektronische Publikation
Fraunhofer IZI ()
Alzheimer's disease

In clinical trials with early Alzheimer’s patients, administration of anti-amyloid antibodies reduced amyloid deposits, suggesting that immunotherapies may be promising disease-modifying interventions against Alzheimer’s disease (AD). Specific forms of amyloid beta (Aβ) peptides, for example post-translationally modified Aβ peptides with a pyroglutamate at the N-terminus (pGlu3, pE3), are attractive antibody targets, due to pGlu3-Aβ’s neo-epitope character and its propensity to form neurotoxic oligomeric aggregates. We have generated a novel anti-pGlu3-Aβ antibody, PBD-C06, which is based on a murine precursor antibody that binds with high specificity to pGlu3-Aβ monomers, oligomers and fibrils, including mixed aggregates of unmodified Aβ and pGlu3-Aβ peptides. PBD-C06 was generated by first grafting the murine antigen binding sequences onto suitable human variable light and heavy chains. Subsequently, the humanized antibody was de-immunized and site-specific mutations were introduced to restore original target binding, to eliminate complement activation and to improve protein stability. PBD-C06 binds with the same specificity and avidity as its murine precursor antibody and elimination of C1q binding did not compromise Fcγ-receptor binding or in vitro phagocytosis. Thus, PBD-C06 was specifically designed to target neurotoxic aggregates and to avoid complement-mediated inflammatory responses, in order to lower the risk for vasogenic edemas in the clinic.