Population-specific design of de-immunized protein biotherapeutics

TL;DR

This paper introduces a population-specific, multi-objective optimization method for designing de-immunized protein therapeutics that retain functionality without relying on structural data, validated through experimental testing.

Contribution

It presents a novel combinatorial optimization approach that accounts for population-specific HLA allele frequencies and predicts functional protein sequences without structural modeling.

Findings

Designed sequences showed reduced immunogenicity in line with predictions.

Experimental testing confirmed the functional integrity of the designed proteins.

Method effectively balances immunogenicity minimization with protein functionality.

Abstract

Immunogenicity is a major problem during the development of biotherapeutics since it can lead to rapid clearance of the drug and adverse reactions. The challenge for biotherapeutic design is therefore to identify mutants of the protein sequence that minimize immunogenicity in a target population whilst retaining pharmaceutical activity and protein function. Current approaches are moderately successful in designing sequences with reduced immunogenicity, but do not account for the varying frequencies of different human leucocyte antigen alleles in a specific population and in addition, since many designs are non-functional, require costly experimental post-screening. Here we report a new method for de-immunization design using multi-objective combinatorial optimization that simultaneously optimizes the likelihood of a functional protein sequence at the same time as minimizing its immunogenicity tailored to a target population. We bypass the need for three-dimensional protein structure or molecular simulations to identify functional designs by automatically generating sequences using probabilistic models that have been used previously for mutation effect prediction and structure prediction. As proof-of-principle we designed sequences of the C2 domain of Factor VIII and tested them experimentally, resulting in a good correlation with the predicted immunogenicity of our model.