Abstract
The immunogenicity of biotherapeutics can bottleneck development pipelines and poses a barrier to widespread clinical application. As a result, there is a growing need for improved deimmunization technologies. We have recently described algorithms that simultaneously optimize proteins for both reduced T cell epitope content and high-level function. In silico analysis of this dual objective design space reveals that there is no single global optimum with respect to protein deimmunization. Instead, mutagenic epitope deletion yields a spectrum of designs that exhibit tradeoffs between immunogenic potential and molecular function. The leading edge of this design space is the Pareto frontier, i.e. the undominated variants for which no other single design exhibits better performance in both criteria. Here, the Pareto frontier of a therapeutic enzyme has been designed, constructed, and evaluated experimentally. Various measures of protein performance were found to map a functional sequence space that correlated well with computational predictions. These results represent the first systematic and rigorous assessment of the functional penalty that must be paid for pursuing progressively more deimmunized biotherapeutic candidates. Given this capacity to rapidly assess and design for tradeoffs between protein immunogenicity and functionality, these algorithms may prove useful in augmenting, accelerating, and de-risking experimental deimmunization efforts.
Highlights
Therapeutic proteins are revolutionizing disease therapy across a broad range of indications and illnesses, and biotherapeutic sales are an increasingly important part of the pharmaceuticals market [1,2]
Once internalized by antigen presenting cells (APCs), a protein is cleaved into small peptide fragments, putative immunogenic segments are loaded into the groove of class II major histocompatibility complex proteins (MHC II), and the complexes are trafficked to the APC surface
Protein therapeutics have created a revolution in disease therapy, providing improved outcomes for prevalent illnesses and conditions while at the same time yielding treatments for diseases that were previously intractable
Summary
Therapeutic proteins are revolutionizing disease therapy across a broad range of indications and illnesses, and biotherapeutic sales are an increasingly important part of the pharmaceuticals market [1,2]. A relatively unique risk factor for protein therapeutics is their inherent potential to induce anti-drug immune responses in human patients [3,4,5]. True immunogenic peptides, termed T cell epitopes, facilitate the formation of ternary MHC II-peptide-T cell receptor complexes with surface receptors of cognate CD4+ T cells [8] This critical molecular recognition event initiates a signaling cascade that drives stimulation of helper T cells, maturation of B cells, and production of circulating antibodies that bind to and clear the foreign therapeutic protein. Detailed knowledge of this process enables protein deimmunization via mutation of key residues in immunogenic epitopes, a methodology commonly known as T cell epitope deletion
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