Directed evolution of drug-like Aβ conformation-specific antibodies

TL;DR

Scientists developed a new method to create better antibodies that target harmful protein clumps linked to Alzheimer's disease.

Contribution

A directed evolution platform was developed to generate high-quality conformational antibodies against Aβ fibrils.

Findings

The approach produced antibodies with higher affinity and specificity than existing clinical candidates.

Antibodies showed reduced off-target binding compared to aducanumab and crenezumab.

The method is applicable to diverse peptide and protein aggregates in human diseases.

Abstract

Monoclonal antibodies that recognize conformational epitopes in protein aggregates are important for research, diagnostic, and therapeutic applications related to neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Unfortunately, it remains challenging to discover and engineer high-quality conformational antibodies that are specific for protein aggregates and possess optimal combinations of three key binding properties, namely high affinity, high conformational specificity, and low off-target binding. Here we report a directed evolution approach for generating high-quality conformational antibodies against Alzheimer’s Aβ fibrils in the native IgG format. Our directed evolution approach uses targeted mutagenesis, yeast surface display, cell sorting, and deep sequencing to identify antibody candidates with optimized binding properties. Notably, we find that this approach yields robust isolation of IgGs with higher affinity, higher conformational specificity, and lower off-target binding than multiple clinical-stage Aβ antibodies, including aducanumab and crenezumab. This antibody engineering platform can be readily applied to generate conformational antibodies against diverse types of peptide and protein aggregates linked to human diseases.

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