Justin T. Hole

A Plaque-Specific Antibody Clears Existing β-amyloid Plaques in Alzheimer's Disease Mice

Aβ Immunotherapy is a promising therapeutic approach for Alzheimers disease. Preclinical studies demonstrate that plaque prevention is possible; however, the more relevant therapeutic removal of existing plaque has proven elusive. Monoclonal antibodies in development target both soluble and insoluble Aβ peptide. We hypothesized that antibody specificity for deposited plaque was critical for plaque removal since soluble Aβ peptide would block recognition of deposited forms. We developed a plaque-specific antibody that targets a modified Aβ peptide (Aβ(p3-42)), which showed robust clearance of pre-existing plaque without causing microhemorrhage. Interestingly, a comparator N-terminal Aβ antibody 3D6, which binds both soluble and insoluble Aβ(1-42), lacked efficacy for lowering existing plaque but manifested a significant microhemorrhage liability. Mechanistic studies suggested that the lack of efficacy for 3D6 was attributed to poor target engagement in plaques. These studies have profound implications for the development of therapeutic Aβ antibodies for Alzheimers disease.

TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques

Wang et al. report that TREM2 protects mice from Alzheimers disease by enabling resident microglia to insulate and alter Aβ plaque structure, thereby limiting neuritic damage.

COMBINATION THERAPY WITH A PLAQUE-SPECIFIC ABETA ANTIBODY AND A BACE INHIBITOR RESULTS IN DRAMATIC PLAQUE REDUCTION IN A DOSE-DEPENDENT MANNER IN AGED PDAPP TRANSGENIC MICE

lowed. Results:High antibody responses were found in both species. In the rabbit, 277.16 118.4 mg/ml plasmaweremeasured after 5 immunizations with no significant differences between the dose groups. Antibody levels declined slightly to 246.66 109.5 mg/ml after a resting period of two months. Low levels of IFNg and IL-17 secreting splenocytes were found in the ELISPOTassays from rabbit splenocytes. Rhesusmonkeys reachedmean antibody levels of 114.2 6 41.67 mg/ml plasma after five immunizations. The isotype profile was high on IgG4 antibodies, indicative of a Th2 immune response. After three immunizations, no IL-17 or IFNg producing cells were found in ELISPOT assays from PBMCs. Conclusions: DNA Ab42 immunization leads to high antibody titers in large mammals, and is likely to produce high antibody levels and a safe (Th2 biased) immune response in humans as well. supported by NIA/NIH P30AG12300-21, Zale Foundation, Rudman Foundation, AWARE, Presbyterian Village North, Freiberger, and Denker Family Funds

MEASUREMENT OF ENDOGENOUS MOUSE TAU IN CEREBROSPINAL FLUID FROM AGED PDAPP MICE FOLLOWING TREATMENT WITH AB-LOWERING COMPOUNDS

Background:Dementia is usually attributable to one or a combination of neuropathologic abnormalities, including Alzheimer amyloid plaques and neurofibrillary tangles. Most demented individuals have at least two types of dementia-related abnormality. Older decedents without abnormalities may be viewed as showing resistance to the relevant pathogenic processes. Others with brain or cognitive reserves may maintain normal cognitive performance even when 1 or 2 types of histopathologic abnormality have developed. We hypothesize essential resilience as a third defense against established neuropathology. Methods: Analyses involved 572 autopsied HAAS participants (Japanese-American men) dying at age 80 or older whose baseline Cognitive Assessment and Screening Instrument (CASI) score had been normal (>1⁄474). End-of-life severe impairment was based on a final CASI score <60. Four overlapping reserve elements were each dichotomized as 0 or 1: (i) negligible brain atrophy, (ii) higher education, (iii) higher occupational complexity, (iv) higher adult life cognitive test scores. A neuropathologic burden index (Neurology, March 2016) was the sum of four histopathologic abnormalities, each scored 0.4 (moderate) or 1.0 (severe) for Alzheimer lesions, microinfarcts, Lewy bodies, and hippocampal sclerosis. Results:Among 159 participants with a neuropathologic burden index of zero, 145 (91%) maintained normal cognition. Among 387 with burden indices 0.4 1.8 (most with two moderate or severe lesion types), the proportions developing severe impairment fell from 49%, to 35%, to 29%, to 25%, to 13% respectively in decedents with zero, 1, 2, 3, or all 4 reserve elements. Of 26 decedents with neuropathologic burden indices >1⁄42, 22 (85%) developed severe cognitive impairment. We continue to search for factors determining essential resilience. Conclusions: In this autopsied cohort, brain and/or cognitive reserves provided a powerful attenuation of cognitive impairment attributable to a panel of neuropathological abnormalities. A hypothesized additional contribution by essential resilience remains to be demonstrated.

A COMPETITIVE EX-VIVO SCREENING ASSAY TO DETERMINE ABETA ANTIBODY MEDIATED PHAGOCYTOSIS AND PLAQUE SPECIFICITY

being the most productive source of recruitment. However, thus far the respondents are predominantly Caucasian, college-educated participants. Other targeted recruitment strategies are needed to increase ethnic minority representation. The registry provides a platform for cohort studies and dementia risk analysis. Further risk assessment including genotyping and cognitive screen will be included in the next phase of the project to further characterize risk profiles in preclinical and symptomatic AD.

OPTIMIZATION OF THE PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) PROPERTIES OF AN ANTI-ABETA ANTIBODY M266 FAB FRAGMENT VARIANT BY SITE-SPECIFIC PEGYLATION

neuronal culture assay with an EC50of approximately 250 pM. Following acute oral treatment with 0, 0.3, 1.0, or 3.0 mg/kg LY3202626, dose-dependent reductions in Ab, sAPPb, and C99 were observed in cortex and hippocampus of PDAPPmice. In beagle dog, acute oral dosing of 1.5 mg/kg LY3202626 resulted in lowering of plasma and CSF Ab 1-x by approximately 80% at the nadir; the CSF Ab 1-x was still reduced by approximately 75% at 24 hours post-dosing. Exposure of LY3202626 in plasma and CSF correlated significantly with pharmacodynamic effects upon Ab in both PDAPP mice and beagle dogs. Conclusions:LY3202626 is a potent and selective inhibitor of the BACE1 and BACE2 enzymes. The robust in vivo effects of LY3202626 are consistent with its in vitro potency and exposure in target compartments. These data support further clinical development of LY3202626 for the treatment of AD.

CHARACTERIZATION OF AMINO TERMINAL TRUNCATIONS OF PLAQUE-ASSOCIATED Aβ AFTER COMBINATION BACE INHIBITOR AND ANTIBODY THERAPY IN AGED PDAPP MICE

TRUNCATIONS OF PLAQUE-ASSOCIATED Ab AFTER COMBINATION BACE INHIBITOR AND ANTIBODY THERAPY IN AGED PDAPP MICE Margaret Racke, John Tzaferis, Justin Hole, Feng Liu, Cynthia DeLong, Patrick May, Michael Hutton, Christer Nordstedt, Ronald DeMattos, Eli Lilly and Company, Indianapolis, Indiana, United States; Eli Lilly and Company, Indianapolis, Indiana, United States; Eli Lilly and Company, Indianapolis, Indiana, United States; Eli Lilly and Company, Ltd., Windlesham, United Kingdom; 5 Eli Lilly and Company, Indianapolis, Indiana, United States. Contact e-mail: racke_margaret@ lilly.com