Development of a therapeutic anti-HtrA1 antibody and the identification of DKK3 as a pharmacodynamic biomarker in geographic atrophy

Autor: Amos Baruch, Kenneth J. Katschke, Victoria Pham, Shadi Toghi Eshghi, Phillip Lai, Andrew Ah Young, Wei-Ching Liang, Jennie R. Lill, Chingwei V. Lee, Wei Li, Menno Van Lookeren Campagne, Johnny Gutierrez, Daniel Kirchhofer, Isabel Figueroa, Scott J. Snipas, Guy S. Salvesen, Irene Tom, Lee Honigberg, Jitendra Kanodia
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
Medical Sciences
Genotype
Proteome
genetic structures
medicine.medical_treatment
Proteomics
Polymorphism
Single Nucleotide
Retina
Small Molecule Libraries
Immunoglobulin Fab Fragments
Macular Degeneration
03 medical and health sciences
proteomics
0302 clinical medicine
In vivo
Geographic Atrophy
Animals
Humans
Medicine
Genetic Predisposition to Disease
Adaptor Proteins
Signal Transducing
Aged
age-related macular degeneration (AMD)
Multidisciplinary
Protease
biology
Proteomic Profiling
business.industry
Serine hydrolase
High-Temperature Requirement A Serine Peptidase 1
Biological Sciences
eye diseases
Antibodies
Anti-Idiotypic
Rats
030104 developmental biology
HTRA1
Disease Progression
030221 ophthalmology & optometry
biology.protein
Cancer research
biomarker
Biomarker (medicine)
Female
sense organs
Antibody
business
Biomarkers
Zdroj: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
0027-8424
Popis: Significance Genome-wide association studies have identified genetic variation at the ARMS2/HTRA1 locus as a risk factor for the development and progression of age-related macular degeneration (AMD). We have developed a potent anti-HtrA1 Fab inhibitor of HtrA1 proteolytic activity in the retina as a potential therapeutic for treating AMD. A set of proteomic analytical tools was established to characterize HtrA1 activity and discover in vivo HtrA1 substrates. These efforts led to the identification of an eye-specific and clinically applicable pharmacodynamic biomarker of anti-HtrA1 Fab activity. Analysis of HtrA1-mediated cleavage of Dickkopf-related protein 3 in the aqueous humor of patients with geographic atrophy provided evidence of anti-HtrA1 Fab activity and information on duration of activity in a phase 1 study.
Genetic polymorphisms in the region of the trimeric serine hydrolase high-temperature requirement 1 (HTRA1) are associated with increased risk of age-related macular degeneration (AMD) and disease progression, but the precise biological function of HtrA1 in the eye and its contribution to disease etiologies remain undefined. In this study, we have developed an HtrA1-blocking Fab fragment to test the therapeutic hypothesis that HtrA1 protease activity is involved in the progression of AMD. Next, we generated an activity-based small-molecule probe (ABP) to track target engagement in vivo. In addition, we used N-terminomic proteomic profiling in preclinical models to elucidate the in vivo repertoire of HtrA1-specific substrates, and identified substrates that can serve as robust pharmacodynamic biomarkers of HtrA1 activity. One of these HtrA1 substrates, Dickkopf-related protein 3 (DKK3), was successfully used as a biomarker to demonstrate the inhibition of HtrA1 activity in patients with AMD who were treated with the HtrA1-blocking Fab fragment. This pharmacodynamic biomarker provides important information on HtrA1 activity and pharmacological inhibition within the ocular compartment.
Databáze: OpenAIRE
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